Intensive irrigation in India has been demonstrated to decrease surface temperature, but the influence of irrigation on humidity and extreme moist heat stress is not well understood. Here we analysed a combination of in situ and satellite-based datasets and conducted meteorological model simulations to show that irrigation modulates extreme moist heat. We found that intensive irrigation in the region cools the land surface by 1 °C and the air by 0.5 °C. However, the decreased sensible heat flux due to irrigation reduces the planetary boundary layer height, which increases low-level moist enthalpy. Thus, irrigation increases the specific and relative humidity, which raises the moist heat stress metrics. Intense irrigation over the region results in increased moist heat stress in India, Pakistan and parts of Afghanistan—affecting about 37–46 million people in South Asia—despite a cooler land surface. We suggest that heat stress projections in India and other regions dominated by semi-arid and monsoon climates that do not include the role of irrigation overestimate the benefits of irrigation on dry heat stress and underestimate the risks.