Excess concentration of aerosols with aerodynamic diameter less than 2.5 μm (PM2.5) in atmosphere has significant implications to both climate and human health. For the first time, this study estimated four decades (1980–2021) trends of PM2.5 in urban locations across Southern Africa using the Modern-Era Retrospective Analysis for Research and Applications Version 2 (MERRA-2) aerosol simulations. The findings show that the highest PM2.5 is recorded during the peak of biomass burning, September-October-November (SON season) in locations selected over Mozambique, Malawi, Zambia, Zimbabwe, Madagascar, Botswana, Namibia, and north of South Africa while during Jun-July-August (JJA season) in locations selected over Southern Mozambique, eastern locations of South Africa, and west of Angola. The lowest PM2.5 concentration is observed during December-January-February (DJF) and March-April-May (MAM) seasons across the region due to increased precipitation which reduces excess PM2.5 in the atmosphere. The annual concentration of PM2.5 in most locations exceeds the recent recommendation by the World Health Organization (WHO, 2021) of 5μg m−3, hence high threat to human health due to long-term exposure to PM2.5. Long-term trends showed a significant increase of PM2.5 over the region during the last four decades, with the highest increment observed during SON season. Implementation of regional measures that can reduce excess PM2.5 concentration is therefore required across the region.