Abstract: Hazardous/lethal compound temperature–humidity heatwaves with a wet bulb temperature (i.e., ≥33°C/35°C) can severely affect human health. The middle and lower reaches of the Yangtze River always experience high-frequency compound temperature–humidity heatwaves. This study investigates the population exposed to these heatwaves in the middle and lower reaches of the Yangtze River for the near-term (2021–2040), medium-term (2041–2060), and long-term (2081–2100) periods using the five-climate model outputs under seven SSPs (Shared Socioeconomic Pathways)—based scenarios (i.e., SSP1-1.9, SSP1-2.6, SSP4-3.4, SSP2-4.5, SSP4-6.0, SSP3-7.0, and SSP5-8.5). These scenarios are obtained from the CMIP6 (Coupled Model Intercomparison Project phase 6) in combination with the demographic characteristics under the Shared Socioeconomic Pathways (i.e., SSP1-5). The results show that during the baseline period of 1995–2014, hazardous/lethal compound temperature–humidity heatwaves occurred at frequencies of approximately 6 d and 3 d in the middle and lower reaches of the Yangtze River, where the longest duration was approximately 10 d and 4 d, respectively. In the future, the frequency and duration of such heatwaves are projected to increase in the long-term period, where the frequency is expected to be approximately 12–39 d and 7–24 d, and the longest duration is as long as 30 d and 14 d, respectively. In the baseline period, the hazardous/lethal compound temperature–humidity heatwaves affected an area of approximately 74.8×10⁴ and 22.3×10⁴ km² in the middle and lower reaches of the Yangtze River, exposing the populations of 170 million and 20 million people of the hazardous/lethal compound temperature–humidity heatwaves, respectively. The impact range and maximum exposed population in the 21st century were observed in the long-term period, accounting for approximately 83%–100% and 32%–98% of the study area, respectively. The exposed population was approximately 1.2–2.5 and 2.5–20.5 times higher than that during the base period in the middle and lower reaches of the Yangtze River, respectively. The population exposed to the lethal compound temperature–humidity heatwaves increased considerably by approximately 40 million–370 million. Spatially, the main areas affected by these heatwaves in the 21st century are Shanghai, northern Zhejiang, southern Jiangsu, southern Anhui, eastern Hunan, and eastern Jiangxi. Overall, forecasting, early warning, and risk prevention of lethal compound temperature–humidity heatwaves must be urgently improved.