As the climate warms, the thickening of the active layer of permafrost has led to permafrost melting and surface collapse, forming thermokarst landforms. These changes significantly impact regional vegetation, soil physicochemical properties, and hydrological processes, thereby exacerbating regional carbon cycling. This study analyzed the relationship between soil respiration rate (Rs), soil temperature (T), and volumetric water content (VWC) in the thermokarst depression zone of the headwater wetlands of Qinghai Lake, revealing their influence on these soil parameters. Results showed a significant positive correlation between soil temperature and Rs (p < 0.001), and a significant negative correlation between VWC and Rs (p < 0.001). The inhibitory effect of VWC on Rs in the thermokarst depression zone was stronger than under natural conditions (p < 0.05). Single-factor models indicated that the temperature-driven model had higher explanatory power for Rs variation in both the thermokarst depression zone (R2 = 0.509) and under natural conditions (R2 = 0.414), while the humidity-driven model had lower explanatory power. Dual-factor models further improved explanatory power, slightly more so in the thermokarst depression zone. This indicates that temperature and humidity jointly drive Rs. Additionally, during the daytime, temperature had a more significant impact on Rs under natural conditions, while increased VWC inhibited Rs. At night, the positive correlation between Rs and temperature in the thermokarst depression zone increased significantly. The temperature sensitivity (Q10) values of Rs were 3.32 and 1.80 for the thermokarst depression zone and natural conditions, respectively, indicating higher sensitivity to temperature changes at night in the thermokarst depression zone. This study highlights the complexity of soil respiration responses to temperature and humidity in the thermokarst depression zone of Qinghai Lake's headwater wetlands, contributing to understanding carbon cycling in wetland ecosystems and predicting wetland carbon emissions under climate change.