Along with its rapid urban development, Ho Chi Minh City (HCMC) in recent years has suffered a high concentration of air pollutants, especially fine particulate matters or PM2.5. A comprehensive study is required to evaluate the air quality conditions and their health impact in this city. Given the lack of adequate air quality monitoring data over a large area of the size of HCMC, an air quality modeling methodology is adopted to address the requirement. Here, by utilizing a corresponding emission inventory in combination with The Air Pollution Model-Chemical Transport Model (TAPM-CTM), the predicted concentration of air pollutants is first obtained for PM2.5, NOx, and SO2. Then by associating the pollutants exposed with the mortality rate from three causes, namely Ischemic Heart Disease (IHD), cardiopulmonary, and lung cancer, the impact of air pollution on human health is obtained for this purpose. Spatial distribution has shown a high amount of pollutants concentrated in the central city with a high density of combustion vehicles (motorcycles and automobiles). In addition, a significant amount of emissions can be observed from stevedoring and harbor activities, including ferries and cargo handling equipment located along the river. Other sources such as household activities also contribute to an even distribution of emission across the city. The results of air quality modeling showed that the annual average concentrations of NO2 were higher than the standard of Vietnam National Technical Regulation on Ambient Air Quality (QCVN 05: 2013 40 µg/m3) and World Health Organization (WHO) (40 µg/m3). The annual average concentrations of PM2.5 were 23 µg/m3 and were also much higher than the WHO (10 µg/m3) standard by about 2.3 times. In terms of public health impacts, PM2.5 was found to be responsible for about 1136 deaths, while the number of mortalities from exposure to NO2 and SO2 was 172 and 89 deaths, respectively. These figures demand some stringent measures from the authorities to potentially remedy the alarming situation of air pollution in HCM City.