This study determined the temporal variation of PM2.5 in ambient air in Thohoyandou and further assessed the associated health risks. The levels of PM2.5 were quantified for a period of 1 year (April 2017-April 2018) using the gravimetric method. There was no significant difference (P-value = 0.18) in concentrations of both PM2.5 samples collected during weekdays (11.29 µg.m-3) and weekends (9.86 µg.m-3). However, higher concentrations of PM2.5 were measured in spring and the lowest was measured in summer. The cancer risk obtained for PM2.5 (2.21 × 10−5, 3 × 10-4, and 5 × 10-4 for infants, children, and adults respectively) in the outdoor air of Thohoyandou has exceeded the limit values by the USEPA and WHO, implying a significant risk for the whole population. For non-carcinogenic risks, the HQ values were 2.60, 4.81, and 2.60 for infants, children, and adults respectively. The HQ value >1 indicates a non-carcinogenic risk to the residents in Thohoyandou and a higher risk to children. Moreover, PM2.5 in Thohoyandou is responsible for 0.15% and 0.13% of deaths resulting from cardiovascular disease and lung cancer respectively for adults above 30 years. PM2.5 is causing adverse health effects in Thohoyandou as deduced from the health risk assessment. Therefore, it is recommended that further epidemiological studies be conducted in Thohoyandou to estimate the burden of disease due to exposure to particulate matter and suitable controlling policies be arranged to reduce particulate matter.