The 6th Assessment of the Intergovernmental Panel on Climate Change projects increasing thermal-associated morbidity and mortality under anthropogenically induced warming. Over 100 indices exist to quantify thermal stress, and among these, the Universal Thermal Climate Index (UTCI) was developed for regional investigations of thermal stress influences on human health. Although by definition a universal index, current applications are mainly limited to Europe. For regions such as Africa, use of the UTCI has been hampered by a lack of available requisite input variables from ground-based meteorological stations. To overcome this, a gridded dataset, derived from ERA5 reanalysis, of UTCI equivalent temperatures was developed by the European Centre for Medium-Range Weather Forecasts. Using this dataset for daily average, minimum and maximum UTCI values, we explore spatiotemporal patterns and changes thereof over annual, seasonal, and monthly scales across southern Africa from 1979 to 2021. Across these scales, 9 of 10 UTCI thermal stress categories were observed, ranging from very strong cold stress to extreme heat stress. Spatially, no thermal stress was most widespread for daily mean values, whereas for daily maximum (minimum) values there was a wider heat (cold) stress incidence, with frequent occurrences of moderate and strong heat stress (slight and moderate cold stress). Interannually, a clear El Niño-Southern Oscillation influence on thermal stress was evident during summer, with El Niño (La Niña) phases extending (reducing) heat stress incidences by up to 13.8% (2.9%). Over the study period, heat stress increased at statistically significant rates in many instances, with the strongest, most widespread increases, for the daily average and maximum (minimum), during spring (summer), averaging 0.28 and 0.29 CÁdecade −1 (0.23 CÁdecade −1 ); few regions experienced statistically significant decreasing trends. Overall, the trend results highlight regions vulnerable to significant thermal climate changes, and thus should be considered in decision-making regarding outdoor activities.