Responses of soil respiration to atmospheric and climatic change will have profound impacts on ecosystem and global carbon (C) cycling in the future. This study was conducted to examine effects on soil respiration of the concurrent driving factors of elevated atmospheric CO2 concentration, air warming, and changing precipitation in a constructed old-field grassland in eastern Tennessee, USA. Model ecosystems of seven old-field species were established in open-top chambers and treated with factorial combinations of ambient or elevated (+300 ppm) CO2 concentration, ambient or elevated (+3 °C) air temperature, and high or low soil moisture content. During the 19-month experimental period from June 2003 to December 2004, higher CO2 concentration and soil water availability significantly increased mean soil respiration by 35.8% and 15.7%, respectively. The effects of air warming on soil respiration varied seasonally from small reductions to significant increases to no response, and there was no significant main effect. In the wet side of elevated CO2 chambers, air warming consistently caused increases in soil respiration, whereas in the other three combinations of CO2 and water treatments, warming tended to decrease soil respiration over the growing season but increase it over the winter. There were no interactive effects on soil respiration among any two or three treatment factors irrespective of time period. Treatment-induced changes in soil temperature and moisture together explained 49%, 44%, and 56% of the seasonal variations of soil respiration responses to elevated CO2, air warming, and changing precipitation, respectively. Additional indirect effects of seasonal dynamics and responses of plant growth on C substrate supply were indicated. Given the importance of indirect effects of the forcing factors and plant community dynamics on soil temperature, moisture, and C substrate, soil respiration response to climatic warming should not be represented in models as a simple temperature response function, and a more mechanistic representation including vegetation dynamics and substrate supply is needed.