It is important to explore air pollution and health effects in developing cities for early prevention rather than waiting for conditions to deteriorate as in the current megacities. This study aims to investigate the short-term health effects of air pollution in a large city in the Mekong Delta Region (MDR) of Vietnam. Air pollution data from January 2015 to December 2018 were collected from the Environmental Monitoring Centre of Can Tho City. The data of respiratory and cardiovascular disease (CVD) admissions in 18 hospitals and medical centers were collected. A time-series regression analysis was conducted using distributed lag models to examine the relationship between the air pollutants and hospitalizations including the delayed effect up to 7 days. The research findings reveal that a 10 μg increase in PM10 was associated with an increase of 2.5% in the risk of respiratory admission for all people and 2.2% in the risk of CVD admission for the elderly on the same day. The analysis stratified by age and sex indicates that PM10 resulted in a higher risk of respiratory admission among children (0–5 years old) and males compared with other groups. PM10 and NO2 were significantly associated with CVD admission among the elderly at lag 4 and 6 days. The effects of other air pollutants (SO2, O3) were not observed in this study. As development continues in this region, there is an urgent need for intervention measures to minimize the health impacts associated with the expected increases in air pollution in the MDR.