Over-the-counter medicines play an important role in community healthcare in Vietnam, particularly with the rise of self-medication during and after the COVID-19 pandemic. This study examines several factors influencing customers’ purchase decisions for over-the-counter medicines at community pharmacies in District 4, Ho Chi Minh City. A mixed-methods approach was used, comprising qualitative interviews with 30 customers and a cross-sectional survey of 400 adults purchasing Over-the-counter medicines at 77 pharmacies from June to August 2022. Convenience sampling with stratification by pharmacy scale and location was applied. Data was collected using a five-point Likert questionnaire, then were analyzed with SPSS 22.0, Cronbach’s alpha, Exploratory Factor Analysis, and multiple linear regression. The results indicate that medicine advertising (β = 0.479), medicine quality (β = 0.357), and reference groups (β = 0.358) significantly influenced purchase decisions, as shown by 54.6% of the variance. Advertising had the strongest effect, reflecting the growing impact of media and digital marketing, while price and packaging were not statistically significant. The findings offer practical implications for pharmacy management and patient counseling.