Carbon efflux from soils is the largest terrestrial carbon source to the atmosphere, yet it remains one of the most uncertain fluxes in the Earth’s carbon budget. A dominant component of this flux is heterotrophic respiration, influenced by several environmental factors, most notably soil temperature and moisture. We developed a mechanistic model from micro to global scale to explore how changes in soil water content and temperature affect soil heterotrophic respiration. Simulations, laboratory measurements, and field observations validate the new approach. Estimates from the model show that heterotrophic respiration has been increasing since the 1980s at a rate of about 1.7% per decade globally. Using future projections of surface temperature and soil moisture, the model predicts a global increase of about 40% in heterotrophic respiration by the end of the century under the worst-case emission scenario, which is driven principally by the reduction of soil moisture rather than temperature increase.