Background and Aim: Coronavirus disease (COVID-19) has been announced as a life-threatening, highly transmissible infectious novel emerging disease worldwide. Rapid detection and epidemiological information are desperately needed to overcome the existing pandemic situation and alleviate national and international crises. Still, to date, there is no significant epidemiological study of COVID-19 available in Bangladesh, especially in the Chattogram division. However, the current study focuses on molecular detection, prevalence, and risk factors associated with COVID-19 in Southern Bangladesh. Materials and Methods: Standard diagnostic protocols through real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) were performed for molecular confirmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Different patient demographics were analyzed for exploring the relationship of four factors – region, sex, age, and symptoms with the accumulated number of COVID-19 cases in the Southern Bangladesh during the period of May 13, 2020, to June 12, 2020. Results: A total of 2954 samples were tested where the cumulative prevalence of circulating SARS-CoV-2 was 29.76% (n=879; 95% CI: 28.11-31.44) in the selected study region. Among the risk factors, the present study revealed that flatland people (35.62%, 95% CI 33.61-37.67, OR=3.13) were more vulnerable to getting infected by SARS-CoV-2 than the people living in hill tracts (13.04%, 95% CI 10.73-15.63). People older than 50 years (34.68%, 95% CI 30.38-39.18) were designated the highest risk than other different age groups. A higher number of COVID-19 cases were confirmed in patients (36.0%, 95% CI 33.77-38.29, OR=1.76) with typical symptoms, but interestingly a significant number of asymptomatic carriers (20.39%, 95% CI 18.13-22.80) also positive for SARS-CoV-2. Conclusion: To the best of our knowledge, this is the first epidemiological report in the Southern Bangladesh for COVID- 19. The study's findings will contribute to health professionals and the policy-makers to take preventive measures against the next outbreak emergency for Bangladesh.