In 60 B.C. (the second year of the Shenjue reign period of Emperor Xuandi of the Han Dynasty), the Western Regions Frontier Command was established. At about the same time, an internal disturbance occurred among the Xiongnu ruling clique, and Xian Shan, Prince Rizhu of the Xiongnu stationed in the Western Regions, led a cavalry of several ten thousand strong to pledge allegiance to the Han imperial court. The Western Han court appointed Zheng Ji as the frontier commander of the Western Regions, with his headquarters in Urli (in modern Luntai County), to administer over the whole region. The local chieftains and principal officials in all parts of the Western Regions all accepted official seals from the Western Han court. The establishment of the Western Regions Frontier Command indicated that the Western Han had begun to exercise state sovereignty over the Western Regions, and that Xinjiang had become a component part of the unitary multi-ethnic Chinese nation.

The government of the Eastern Han Dynasty (25-220) appointed first a frontier commander, and then a governor, of the Western Regions to continue to exercise military and political administration over all parts of the western territory both north and south of the Tianshan Mountains. In 221, the Kingdom of Wei (220-265) of the Three Kingdoms Period (220-265, the other two kingdoms being Shu and Wu) inherited the Han practice, stationing a garrison commander at Gaochang (Turpan) to rule the Western Regions. Later, it also appointed a governor to administer affairs concerning the ethnic groups in the Western Regions. In the last years of the Western Jin Dynasty (265-316), Zhang Jun, founder of the Former Liang Regime (301-376), sent an expedition to the Western Regions, occupied the Gaochang area and established Gaochang Prefecture. The Northern Wei Dynasty (386-534) set up Shanshan and Yanqi garrison commands to strengthen its administration of the Western Regions.

During the Sui and Tang dynasties, the central government strengthened its rule over Xinjiang. In the last years of the sixth century, the Sui Dynasty (581-618) unified the Central Plains. When Emperor Yangdi (r. 604-618) ascended the throne, one of his first acts was to send Pei Ju, Vice Minister of Personnel, to Zhangye and Wuwei to supervise trade with the Western Regions and investigate local conditions. In 608, troops of the Sui Dynasty occupied Yiwu (Araturuk), built a city wall there, and established the three prefectures of Shanshan (modern Ruoqiang, or Qarkilik), Qiemo (southwest of modern Qiemo, or Qarqan) and Yiwu (within the territory of modern Hami).

In the early seventh century, the Tang Dynasty replaced the Sui. In 630, Yiwu, together with the seven cities under its jurisdiction, changed its allegiance from the Western Turks to the Tang Dynasty, which established Western Yizhou Prefecture (later Yizhou Prefecture). In 640, Tang troops crushed a rebellion staged by the Qu ruling house (501-640) of the Gaochang Kingdom in collusion with the Turks, and established a Xizhou Prefecture in Gaochang and a Tingzhou (Bexibalik) Prefecture in Kaganbu (modern Jimsar). In the same year, the Tang court set up the Anxi Frontier Command in Gaochang. This was the first high-ranking military and administrative organ established by the Tang Dynasty in the Western Regions. Later, it was moved to Kuche, and its name was changed to the Grand Anxi Frontier Command. After defeating the Western Turks, the Tang Dynasty unified all parts of the Western Regions, and in 702 established the Beiting Frontier Command in Tingzhou (later upgraded to Grand Beiting Frontier Command) to take charge of military and administrative affairs in the north of the Tianshan Mountains and the east of Xinjiang, while the Grand Anxi Frontier Command supervised military and administrative affairs in the vast areas south of the Tianshan Mountains and west of the Congling Mountain Range. Emperor Xuanzong (r. 712-756) of the Tang Dynasty established a Qixi Military Governorship to supervise both frontier commands. Qixi was one of the eight major military governorships at that time in the country.

The Tang central government instituted a system of separate administrations for the Han and the people of the other ethnic groups in the Western Regions. That is, it adopted the same administrative system of prefecture, sub-prefecture, county, township and li (neighborhood or village) as in the inland areas in Yizhou, Xizhou and Tingzhou, where most Han were concentrated. In addition, the equal-field system (the farmland system of the Tang Dynasty) and taxation system of payment in kind and labor were adopted, as well as the system of prefectural military commands. In the areas inhabited by other ethnic groups, the Tang rulers governed through the traditional chiefs and headmen, who were granted civil and military titles but allowed to manage local affairs according to their own customs. At the same time, the central government stationed garrisons in Qiuci, Yutian, Shule and Suiye (or Suyab, formerly Yanqi), which were known as the "four garrison commands of Anxi."