The Eocene is the maximum flooding season in the Qaidam Basin during Cenozoic. The palaeogeography research has always focused on the edge of the basin, and there is no detailed study about the central basin. The lithofacies and paleo-salinity of typical wells in the basin were investigated, and the differences in these data between wells were analyzed. It is believed that there is a central paleo-uplift in the Qaidam Basin, which has not been reported before. The paleo-uplift caused significant disparity in the lithofacies between the Western Qaidam depression and the Yiliping depression: the former is dominated by dark mudstone, lime mudstone, argillaceous limestone, and evaporites, with obvious physical and chemical mixed deposits origin; dissimilarly, the latter is dominated by dark gray mudstone and sandy mudstone, which is only a typical physical deposition. In addition, the salinity of the Yiliping depression is 12‰-16‰ by means of trace elements—Boron, while the salinity is over 16‰ in most of the Western Qaidam depression, the Yingxi region in which deposits halite with a total thickness of more than 100m, meaning that its salinity exceeds 260‰. The above results indicate that it is the existence of the central paleo-uplift that blocked the lake water circulation in the sedimentary basin, causing the most important recharge rivers at that time, which are located at the margin of the Yiliping depression, to supply the Western Qaidam depression with little fresh water. As a result, the salinity of the sedimentary waters in the Western Qaidam depression increases under the background of arid climate, and finally the salt rock is precipitated in the partially closed lagoon area. Obstructed by the central paleo-uplift, a large number of microorganisms prosper in the Western Qaidam depression, creating conditions for the formation of high-quality source rocks and microbial reservoirs.