The Shia Safavid government was established in the 16th century AD (10th century AH) in the vicinity of the 200-year-old Ottoman government and the newly established Uzbek government, both of which were Sunni. The religious policy of Shah Ismail I (1501-1524 AD/907-930 AH) was based on the expansion of Shiism, which was in contrast with the religious policy of his neighbors, who were preachers and promoters of the Sunni religion. In addition to the fact that this issue caused religious disputes and repeated wars with the Safavids from both sides, it led to the convergence of the two Ottoman and Uzbek governments against the Safavids. The purpose of this research is to examine how Ottoman and Uzbek political relations were established and its consequences on the Safavids in the 16th century AD, with a descriptive-analytical method. The findings show that the formation and stabilization of Safavid rule, the development of its territory, and the Shiiteization of society, which was accompanied by the increase in the number of Shiites, caused concern to the Ottoman and Uzbek governments. Therefore, due to the common religion and the difference in religious policy with the Safavids, the two governments, with the aim of overthrowing and resorting to the issuance of Takfiri fatwas and the declaration of jihad, strengthened relations with each other against this government and established the idea of political and military unity by sending ambassadors, writing letters and sending military aid.