By 1510 the Uzbeks had completed their conquest of Central Asia, including the territory of the present-day Uzbekistan. Of the states they established, the most powerful, the Khanate of Bukhoro, centered on the city of Bukhoro. The khanate controlled Mawarannahr, especially the region of Tashkent, the Fergana Valley in the east, and northern Afghanistan. A second Uzbek state was established in the oasis of Khorazm at the mouth of the Amu Darya. The Khanate of Bukhoro was initially led by the energetic Shaybanid Dynasty. The Shaybanids competed against Iran, which was led by the Safavid Dynasty, for the rich far-eastern territory of present-day Iran. The struggle with Iran also had a religious aspect because the Uzbeks were Sunni Muslims, and Iran was Shia.

Near the end of the sixteenth century, the Uzbek states of Bukhoro and Khorazm began to weaken because of their endless wars against each other and the Persians and because of strong competition for the throne among the khans in power and their heirs. At the beginning of the seventeenth century, the Shaybanid Dynasty was replaced by the Janid Dynasty.

Another factor contributing to the weakness of the Uzbek khanates in this period was the general decline of trade moving through the region. This change had begun in the previous century when ocean trade routes were established from Europe to India and China, circumventing the Silk Route. As European-dominated ocean transport expanded and some trading centers were destroyed, cities such as Bukhoro, Merv, and Samarqand in the Khanate of Bukhoro and Khiva and Urganch (Urgench) in Khorazm began to steadily decline.

The Uzbeks' struggle with Iran also led to the cultural isolation of Central Asia from the rest of the Islamic world. In addition to these problems, the struggle with the nomads from the northern steppe continued. In the seventeenth and eighteenth centuries, Kazak nomads and Mongols continually raided the Uzbek khanates, causing widespread damage and disruption. In the beginning of the eighteenth century, the Khanate of Bukhoro lost the fertile Fergana region, and a new Uzbek khanate was formed in Quqon.