Abstract: The Middle Miocene Climatic Optimum (MMCO) is a short-term climate warming event interrupting the background of Cenozoic climate cooling. Study on the environmental characteristics based on sediments is important for predicting the trend of climate change with the global warming in the future. There are few records of the MMCO in the extreme arid interior of Asia, and the controlling factors of paleoclimate changes are still unclear. The mineral assemblages of the Miocene sediments from the Huatugou section in the northern Qaidam Basin were analyzed, the regional response to the global climate event and the environmental change in the Qaidam Basin during early-middle Miocene were revealed, and the paleoclimate evolution including the shifting and driving mechanisms of relative moisture index of clay minerals were focused. Results show that during the early-middle Miocene in Qaidam Basin, the climate during 17.2～15.2 Ma was the warmest and wettest, which should belong to the MMCO and mainly affected by the global climate. The climate in the basin began to fluctuate and became dried during 15.2～12.4 Ma. The basin was affected by the regional geological structure and the Middle Miocene cooling event. From 12.4 to 11.3 Ma, Qaidam Basin continued to dry out, mainly under the influence of global climate again. We pointed out that the global climate change trend and regional tectonic movement influenced the early and middle Miocene climate in Qaidam Basin.