Euthydemus, a Magnesian Greek according to Polybius and possibly satrap of Sogdiana, overthrew Diodotus II around 230 BC and started his own dynasty. Euthydemus's control extended to Sogdiana, going beyond the city of Alexandria Eschate founded by Alexander the Great in Ferghana:

"And they also held Sogdiana, situated above Bactriana towards the east between the Oxus River, which forms the boundary between the Bactrians and the Sogdians, and the Iaxartes River. And the Iaxartes forms also the boundary between the Sogdians and the nomads."

 Euthydems was attacked by the Seleucid ruler Antiochus III  around 210 BC. Although he commanded 10,000 horsemen, Euthydemus initially lost a battle on the Arius and had to retreat. He then successfully resisted a three-year siege in the fortified city of  Bactra  (modern Balkh), before Antiochus finally decided to recognize the new ruler, and to offer one of his daughters to Euthydemus's son Demetrius around 206 BC. Classical accounts also relate that Euthydemus negotiated peace with Antiochus III by suggesting that he deserved credit for overthrowing the original rebel Diodotus, and that he was protecting Central Asia from nomadic invasions thanks to his defensive efforts:

"...for if he did not yield to this demand, neither of them would be safe: seeing that great hords of Nomads were close at hand, who were a danger to both; and that if they admitted them into the country, it would certainly be utterly barbarised."

Following the departure of the Seleucid army, the Bactrian kingdom seems to have expanded. In the west, areas in north-eastern Iran may have been absorbed, possibly as far as into Parthia, whose ruler had been defeated by Antiochus the Great. These territories possibly are identical with the Bactrian satrapies of Tapuria and Traxiane.

To the north, Euthydemus also ruled Sogdiana and Ferghana, and there are indications that from Alexandria Eschate the Greco-Bactrians may have led expeditions as far as Kashgar and Urumqi in Chinese Turkestan, leading to the first known contacts between China and the West around 220 BC. The Greek historian Strabo too writes that:

"they extended their empire even as far as the Seres (Chinese) and the Phryni"

Several statuettes and representations of Greek soldiers have been found north of the Tien Shan, on the doorstep to China, and are today on display in the Xinjiang museum at Urumqi (Boardman).

Greek influences on Chinese art have also been suggested (Hirth,Rostoytzeff). Designs with rosette flowers, geometric lines, and glass inlays, suggestive of Hellenistic influences, can be found on some early Han bronze mirrors, dated between 300-200 BC.

 Numismatics also suggest that some technology exchanges may have occurred on these occasions: the Greco-Bactrians were the first in the world to issue Curo-nickel (75/25 ratio) coins, an alloy technology only known by the Chinese at the time under the name "White copper" (some weapons from the Warring States Period were in copper-nickel alloy). The practice of exporting Chinese metals, in particular iron, for trade is attested around that period. Kings Agathocles and Pantaleon made these coin issues around 170 BC. Copper-nickel would not be used again in coinage until the 19th century.

The presence of Chinese people in India from ancient times is also suggested by the accounts of the "Cinas" in the Mahabharata and the Manu Smriti.

The Han Dynasty explorer and ambassador Zhang Qian visited Bactria in 126 BC, and reported the presence of Chinese products in the Bactrian markets:

""When I was in Bactria (Daxia)", Zhang Qian reported, "I saw bamboo canes from Qiong and cloth made in the province of Shu (territories of southwestern China). When I asked the people how they had gotten such articles, they replied, "Our merchants go buy them in the markets of Shendu (India).""

Upon his return, Zhang Qian informed the Chinese emperor Han  Wudi of the level of sophistication of the urban civilizations of Ferghana, Bactria and Parthia, who became interested in developing commercial relationship them:

"The Son of Heaven on hearing all this reasoned thus: Ferghana (Dayuan) and the possessions of Bactria (Daxia) and Parthia (Anxi) are large countries, full of rare things, with a population living in fixed abodes and given to occupations somewhat identical with those of the Chinese people, and placing great value on the rich produce of China"

A number of Chinese envoys were then sent to Central Asia, triggering the development of the Silk Road  from the end of the 2nd century BC.

The Indian emperor, founder of the Mauryan dynasty, had re-conquered northwestern India upon the death of  Alexander the Great around 322 BC. However, contacts were kept with his Greek neighbours in the Seleucid Empire, , a dynastic alliance or the recognition of intermarriage between Greeks and Indians were established (described as an agreement on Epigamia in Ancient sources), and several Greeks, such as the historian Megasthenes, resided at the Mauryan court. Subsequently, each Mauryan emperor had a Greek ambassador at his court.

Chandragupta's grandson Ashoka converted to the Buddhist faith and became a great proselytizer in the line of the traditional Pali canon of  Theravada Buddhism, directing his efforts towards the Indian and the Hellenistic worlds from around 250 BC. According to the Edicts of Ashoka, set in stone, some of them written in Greek, he sent Buddhist emissaries to the Greek lands in Asia and as far as the Mediterranean. The edicts name each of the rulers of the Hellenistic world at the time.

"The conquest by Dharma has been won here, on the borders, and even six hundred  yojanas  (4,000 miles) away, where the Greek king Antiochos rules, beyond there where the four kings named Ptolemy, Antigonos, Mages and Alexandra rule, likewise in the south among the Cholas, the, and as far as." (Edicts of Ashoka, 13th Rock Edict, S. Dhammika).

Some of the Greek populations that had remained in northwestern India apparently converted to Buddhism:

"Here in the king's domain among the Greeks, the Kambojas, the Nabhakas, the Nabhapamkits, the Bhojas, the Pitinikas, the Andhras and the Palidas, everywhere people are following Beloved-of-the-Gods' instructions in Dharma. (Edicts of Ashoka,13th Rock Edict, S. Dhammika).

Furthermore, according to Pali sources, some of Ashoka's emissaries were Greek Buddhist monks, indicating close religious exchanges between the two cultures:

"When the thera (elder) Moggaliputta, the illuminator of the religion of the Conqueror (Ashoka), had brought the (third) council to an end… he sent forth theras, one here and one there: …and to Aparantaka (the "Western countries" corresponding to Gujarat and Sindh) he sent the Greek ( Yona) named Dhammarakkhita... and the thera Maharakkhita he sent into the country of the Yona". Mahavamsa XII).

Greco-Bactrians probably received these Buddhist emissaries (At least Maharakkhita, lit. "The Great Saved One", who was "sent to the country of the Yona") and somehow tolerated the Buddhist faith, although little proof remains. In the 2nd century CE, the Christian dogmatist Clement of Alexandria recognized the existence of Buddhist Sramanas  among the Bactrians ("Bactrians" meaning "Oriental Greeks" in that period), and even their influence on Greek thought:

"Thus philosophy, a thing of the highest utility, flourished in antiquity among the barbarians, shedding its light over the nations. And afterwards it came to Greece. First in its ranks were the prophets of the Egyptians; and the Chaldeans among the Assyrians; and the Druids among the Gauls; and the Sramanas among the Bactrians ("Σαρμαναίοι Βάκτρων"); and the philosophers of the Celts; and the Magi of the Persians, who foretold the Saviour's birth, and came into the land of Judea  guided by a star. The Indian gymnosophists are also in the number, and the other barbarian philosophers. And of these there are two classes, some of them called Sramanas ("Σαρμάναι"), and others Brahmins ("Βραφμαναι")."

Demetrius, the son of Euthydemus, started an invasion of India from 180 BCE, a few years after the Mauryan empire  had been overthrown by the Sunga dynasty. Historians differ on the motivations behind the invasion. Some historians suggest that the invasion of India was intended to show their support for the Mauryan empire, and to protect the Buddhist faith from the religious persecutions of the Sungas as alleged by Buddhist scriptures (Tarn). Other historians have argued however that the accounts of these persecutions have been exaggerated (Thapar, Lamotte).

 Demetrius may have been as far as the imperial capital Pataliputra  in eastern India (today Patna). However, these campaigns are typically attributed to Menander. The invasion was completed by 175 BC. This established in northern India what is called the Indo Greek Kingdom, which lasted for almost two centuries until around AD 10. The Buddhist faith flourished under the Indo-Greek kings, foremost among them Menander I. It was also a period of great cultural syncretism, exemplified by the development of Greco-Buddhism.

Back in Bactria, Eucratides, either a general of Demetrius or an ally of the Seleucids, managed to overthrow the Euthydemid dynasty and establish his own rule around 170 BC, probably dethroning Antimachus I and Antimachus II. The Indian branch of the Euthydemids tried to strike back. An Indian king called Demetrius (very likely Demetruis II ) is said to have returned to Bactria with 60,000 men to oust the usurper, but he apparently was defeated and killed in the encounter:

"Eucratides led many wars with great courage, and, while weakened by them, was put under siege by Demetrius, king of the Indians. He made numerous sorties, and managed to vanquish 60,000 enemies with 300 soldiers, and thus liberated after four months, he put India under his rule"

Eucratides campaigned extensively in northwestern India, and ruled on a vast territory as indicated by his minting of coins in many Indian mints, possibly as far as the Jhelum River in Punjab. In the end however, he was repulsed by the Indo-Greek king Menander I, who managed to create a huge unified territory.

In a rather confused account, our historian explains that Eucratides was killed on the field by "his son and joint king", who would be his own son, either Eucratides II or Heliocles I(although there are speculations that it could be his enemy's son Demetrius II). The son drove over Eucratides' bloodied body with his chariot and left him dismembered without a sepulchre:

"As Eucratides returned from India, he was killed on the way back by his son, whom he had associated to his rule, and who, without hiding his parricide, as if he didn't kill a father but an enemy, ran with his chariot over the blood of his father, and ordered the corpse to be left without a sepulture"

Concurrently, and possibly during or after his Indian campaigns, Eucratides' Bactria was attacked and defeated by the Parthian king Mithridates I, possibly in alliance with partisans of the Euthydemids:

"The Bactrians, involved in various wars, lost not only their rule but also their freedom, as, exhausted by their wars against the Sogdians, the Arachotes, the Dranges, the Arians and the Indians, they were finally crushed, as if drawn of all their blood, by an enemy weaker than them, the Parthians."

Following his victory, Mithridates I gained Bactria's territory west of the Arius, the regions of Tapuria and Traxiane:

"The satrapy Turiva and that of Aspionus were taken away from Eucratides by the Parthians."

In the year 141 BCE, the Greco-Bactrians seem to have entered in an alliance with the Seleucid king Demetrius II to fight again against Parthia:

"The people of the Orient welcomed his (Demetrius II) arrival, partly because of the cruelty of the Arsacid, king of the Parthians, partly because, used to the rule of the Macedonians, they disliked the arrogance of this new people. Thus, Demetrius, supported by the Persians, Elymes, Bactrians, routed the Parthians in numerous battles. At the end, trumped by a false peace, he was taken prisoner."

The 5th century historian Orosius  declares that Mithridates I managed to occupy territory between the Indus and the Hydaspes towards the end of his reign, circa 138 BCE, before his kingdom was weakened by his death in 136 BCE.

 Helicoles I ended up ruling in what territory remained. The defeat, both in the west and the east, may have left Bactria very weakened and open to the nomadic invasions.

According to the Han Chronicles, following a crushing defeat in 162 BC by the Xiongnu (Huns), the nomadic tribes of the Yuezhi fled from the Tarim Basin towards the west, crossed the neighbouring urban civilization of the "Ta-Yuan " (probably the Greek possessions in Ferghana), and resettled north of the Oxus in modern-day Kazakhstan and Uzbekistan, in the northern part of the Greco-Bactrian territory. The Ta-Yuan remained a healthy and powerful urban civilization which had numerous contacts and exchanges with China from 130 BC.

The Yuezhi apparently occupied the Greco-Bactrian territory north of the Oxus during the reign of Eucratides, who was busy fighting in India against the Indo-Greeks.

Around 140 BC, eastern Scythians (the Saka, or Sacaraucae of Greek sources), apparently being pushed forward by the southward migration of the Yuezhi started to invade various parts of Parthia and Bactria. Their invasion of Parthia is well documented, in which they attacked in the direction of the cities of Merv, Hecatompolis and Ectabana. They managed to defeat and kill the Parthian king Phraates II, son of Mithridates I, routing the Greek mercenary troops under his command (troops he had acquired during his victory over Antiochus VII). Again in 123 BC, Phraates's successor, his uncle Artabanus I was killed by the Scythians.

It seems that Bactria was also attacked and strongly diminished during the same massive movement of the Scythians. The destruction of the Greco-Bactrian city of Ai Khanoum, dated to around 140 BC, is regularly attributed to them. The Scythians would be further displaced to the South and South-East into Afghanistan and India, under the pressure of the Yuezhi.

The culture of these nomadic invaders is apparently documented by such archaeological sites as   Tillia Tape, is northwestern Afghanistan.

When Zhang Qian visited the Yuezhi in 126 BC, trying to obtain their alliance to fight the Xiongnu, he explained that the Yuezhi were settled north of the Oxus but also held under their sway the territory south of Oxus, which makes up the remaining of Bactria.

According to Zhang Qian, the Yuezhi represented a considerable force of between 100,000 and 200,000 mounted archer warriors, with customs identical to those of the Xiongnu which would probably have easily defeated Greco-Bactrian forces (in 208 BC when the Greco-Bactrian king Euthydemus I confronted the invasion of the Seleucid king Antiochus III the Great, he commanded 10,000 horsemen). Zhang Qian actually visited Bactria (named Daxia in Chinese) in 126 BC, and portrays a country which was totally demoralized and whose political system had vanished, although its urban infrastructure remained:

" Daxia (Bactria) is located over 2,000 li southwest of Dayuan  , south of the Gui (Oxus) river. Its people cultivate the land and have cities and houses. Their customs are like those of Dayuan  . It has no great ruler but only a number of petty chiefs ruling the various cities. The people are poor in the use of arms and afraid of battle, but they are clever at commerce. After the Great Yuezhi moved west and attacked Daxia, the entire country came under their sway. The population of the country is large, numbering some 1,000,000 or more persons. The capital is called the city of Lanshi (Bactra) and has a market where all sorts of goods are bought and sold."

The Yuezhi further expanded southward into Bactria around 120 BC, apparently further pushed out by invasions from the northern Wu-Sun. It seems they also pushed Scythian tribes before them, which continued to India, where they came to be identified as Indo-ScythiansThe invasion is also described in western Classical sources from the 1st century BC, with different names than those used by the Chinese:

"The best known tribes are those who deprived the Greeks of Bactriana, the Asii, Pasiani, ,Tochari, and Sacarauli, who came from the country on the other side of the Jaxartes, opposite the Sacae and Sogdiani."

Around that time the king Heliocles abandoned Bactria and moved his capital to the valley, from where he ruled his Indian holdings. Having left the Bactrian territory, he is technically the last Greco-Bactrian king, although several of his descendants, moving beyond the Hindu Kush, would form the western part of the Indo Greek Kingdom. The last of these "western" Indo-Greek kings,Hermaeus, would rule until around 70 BC, when the Yuezhi again invaded his territory in the Paropamisadae (while the "eastern" Indo-Greek kings would continue to rule until around AD 10 in the area of the Punjab).

Overall, the Yuezhi remained in Bactria for more than a century. They became Hellenized to some degree, as suggested by their adoption of the Greek alphabet to write their Iranian language, and by numerous remaining coins, minted in the style of the Greco-Bactrian kings, with the text in Greek.

Around 12 BC the Yuezhi then movedfurther to northern India where they established the Kushan Empire.