Geological evidence shows that the Asian inland environment experienced enhanced aridity from the Early to the Late Eocene. This enhanced Eocene aridity in the Asian inland was related to combined impacts from global cooling, topographic uplift and land–sea reorganization. However, the primary cause of the enhanced Eocene aridity in this region is still under debate and varies between global cooling and early Tibetan Plateau uplift. To distinguish between the importance of these factors, we evaluate the climatic impacts of these factors from a modeling point of view. Consistent with geological evidence, our simulations support the observed enhanced Eocene aridity in the Asian inland. Both global cooling (induced by atmospheric CO2 decrease) and topographic uplift contributed to intensified Asian inland aridity, while land–sea redistribution did not. The uplift of the central Tibetan Plateau during the early stage of the India–Asia collision is emphasized more to be responsible for the long-term Asian inland aridification during the Eocene, playing at least an equally important role as the global cooling induced by decrease in atmospheric CO2. •Climate simulations support the observed enhanced Eocene aridity in the Asian inland.•Both the early uplift of Tibetan Plateau and the global cooling played important roles in the enhanced aridity.•The early uplift of Tibetan Plateau contributed to the long-term Asian inland aridification during the Eocene.