This paper is the result of oil and gas geological exploration engineering. Objective Kuqa Depression is rich in oil and gas resources, but the study of tectonic–thermal evolution related to oil and gas generation and preservation is very weak. Methods In this study, the apatite fission track test analysis and thermal history simulation were carried out on typical drilling samples in the eastern part of Kuqa Depression. The tectonic–thermal evolution history of the eastern part of Kuqa Depression since Mesozoic was accurately reconstructed, and the maturity evolution period of source rocks was evaluated. Results The apatite fission track ages measured by in–situ LA–ICP–MS are between 77.7 Ma and 104.5 Ma, which are much smaller than the stratigraphic age, and the rapid uplift events of Late Cretaceous are effectively recorded. The thermal history simulation reveals that Kuqa Depression has experienced two periods of rapid uplift since Jurassic (Early Cretaceous–Late Eocene (120–40 Ma) and Late Miocene–present (10–0 Ma)), which are caused by the remote effect of the collision between Lhasa plate, Indian plate and the southern margin of Eurasia plate. Conclusions The differential tectonic uplift in Kuqa Depression is caused by the subduction and compression of the southern Tianshan Mountains gradually advancing from north to south. The Jurassic source rocks in Kuqa Depression show a multi–stage mature evolution model under the influence of multi–stage subsidence. Affected by tectonic uplift events, the Jurassic source rocks mature evolution was at a stagnation stage from early Cretaceous to late Eocene and late Miocene. This study determines the tectonic–thermal evolution history of eastern Kuqa Depression since Mesozoic, and clarifies the mature evolution process of main source rocks, which have important guiding significance for regional tectonic evolution and next oil and gas exploration.