Lake Qinghai has shrunk and then expanded over the past few decades. Quantifying the contributions of climate change and human activities to lake variation is important for water resource management and adaptation to climate change. In this study, we calculated the water volume change of Lake Qinghai, analyzed the climate and land use changes in Lake Qinghai catchment, and distinguished the contributions of climate change and local human activities to water volume change. The results showed that lake water volume decreased by 9.48 km³ from 1975 to 2004 and increased by 15.18 km³ from 2005 to 2020. The climate in Lake Qinghai catchment is becoming warmer and more pluvial, and the changes in land use have been minimal. Based on the Soil and Water Assessment Tool (SWAT), land use change, climate change and interaction effect of them contributed to 7.46%, 93.13% and −0.59%, respectively, on the variation in surface runoff into the lake. From the perspective of the water balance, we calculated the proportion of each component flowing into and out of the lake and found that the contribution of climate change to lake water volume change was 97.55%, while the local human activities contribution was only 2.45%. Thus, climate change had the dominant impact on water volume change in Lake Qinghai.