The Tethys Sea extended into the Kuqa Depression from the Paleocene to the late Eocene and provided an abundant provenance for the deposition of evaporite sequences. Until now, detailed research on the history of transgressions during the late Paleocene-early Eocene in the Kuqa Depression has been limited. Therefore, in this study, we took the upper Paleocene Talak section and the lower Eocene Xiaokuzibai section in the western part of the Depression as the research objects and analyzed the petrology, the carbon and oxygen isotopes of carbonate rocks, and the sulfur and strontium isotopes of gypsum rocks to systematically study the above issues. The delta C-13, delta O-18 and delta S-34 values of the upper Paleocene evaporite sequences were determined to be between 4.2 parts per thousand and 5.7 parts per thousand, between -5.2 parts per thousand and 2.4 parts per thousand, and between 16.5 parts per thousand and 17.9 parts per thousand, respectively. The delta C-13, delta O-18, delta S-34, and(87)Sr/Sr-86 values of the lower Eocene evaporite sequences were determined to be between -6.9 parts per thousand and -2.0 parts per thousand, between -9.0 parts per thousand and -4.5 parts per thousand, between 10.5 parts per thousand and 17.0 parts per thousand, and between 0.708642 and 0.709883, respectively. The analysis results show that the evaporite sequence of the upper Paleocene was formed by transgression. The deposition of the evaporite sequence changed from continental to marine deposition, and then gradually transitioned to continental during the Early Eocene. This paper is of great significance for reconstructing the history of transgressions in the Tethys tectonic realm during this period.