The Qaidam Basin (QB) in the northeastern Tibetan Plateau held a mega-lake system during the Pliocene. Today, the lower elevations in the basin are hyperarid. To understand the mechanisms behind this system change, we applied the Weather Research and Forecasting model for dynamical downscaling of ECHAM5 global climate simulations for present-day (PD) and mid-Pliocene (PLIO) conditions. In PLIO, the annual water balance (∆S) of the QB is higher than that in PD, resulting from a stronger moisture influx across the western border in winter, spring, and autumn and a weaker moisture outflux across the eastern border in summer. The atmospheric water transport across both borders is influenced by the mid-latitude westerlies throughout the year. The jet stream over the QB is stronger in PLIO in winter, spring, and autumn, causing stronger moisture input at the basin’s western border in these seasons. In summer, the jet strength over the QB decreases in PLIO. Meanwhile, the East Asian Summer Monsoon (EASM) intensifies and migrates to the Northwest, transporting moisture into the QB. Thus, the weaker moisture output through the eastern border in summer is a combined result of weakened jet strength and the strengthening of the EASM. Therefore, the differences in ∆S between PLIO and PD are coupled with changes in the mid-latitude westerlies and the EASM. Given that the mid-Pliocene climate is an analog of the projected warm climate of the near future, our study contributes to a better understanding of the impacts of climate change in Central Asia.