Heat waves are among the deadliest natural hazards affecting the United States (US). Therefore, understanding the physical mechanisms modulating their occurrence is essential for improving their predictions and future projections. Using observational data and model simulations, this study finds that the interannual variability of the tropical Atlantic warm pool (AWP, measured as the area enclosed by the 28.5°C sea surface temperature isotherm) modulates heat wave occurrence over the US Great Plains during boreal summer. For example, a larger than normal AWP enhances atmospheric convection over the Caribbean Sea, driving an upper tropospheric anticyclonic anomaly over the Gulf of Mexico and Great Plains, which strengthens subsidence, reduces cloud cover, and increases surface warming. This circulation anomaly thus weakens the Great Plains low-level jet (GPLLJ) and associated moisture transport into the Great Plains, leading to drought conditions and increased heat wave occurrence for most of the US east of the Rockies.