Description: Highlights • Closure of the Tethyan Seaway led to precipitation increase in South Asia but decrease in North Africa. • Closure of the Tethyan Seaway led to enhanced moisture transport from North Africa to South Asia. • Global cooling led to precipitation decrease in North Africa and South Asia during the MMCT. Abstract The Middle Miocene was a period of prominent climatic change, marked by the Mid-Miocene Climatic Optimum (MMCO) and the subsequent global cooling due to a decline of the atmospheric CO2 concentrations (pCO2). In addition to this, the closure of the Tethyan Seaway driven by the Arab-Eurasia collision also had an important effect on the paleoclimatic changes during this period. In this study, we use the Community Earth System Model 1.2.2 (CESM 1.2.2) to simulate the effects of global cooling (i.e. pCO2 decline) and the closure of the Tethyan Seaway on the North African and South Asian climates. Our results show that the global cooling led to a precipitation decrease over both North Africa and South Asia, whereas the closure of the Tethyan Seaway resulted in a precipitation decrease over North Africa but an increase over South Asia. The opposite effects over North Africa and South Asia are due to an increased moisture transport from North Africa to South Asia induced by stronger summer atmospheric circulation when the Tethyan Seaway is closed. We further show that the reconstructed records of drying conditions over North Africa during the warming period from the late Early Miocene to the early Middle Miocene from previous studies can be partly explained by the narrowing of the Tethyan Seaway and its climatic continuing deterioration due to the subsequent final closure and global cooling. Both are precursory conditions for the formation of the Sahara desert. The stronger South Asian monsoon during the Middle Miocene transient cooling period found in previous studies can be partially attributed to the final closure of the Tethyan Seaway.