Objective: To examine gender and residence differentials in the association between physical activity (PA) and academic success among college students attending historically black colleges and universities (HBCU) in Mississippi. Methods: Participants were college students (n=285) that attended a rural or urban HBCU in September 2017. Multivariate linear regression analysis was conducted to estimate the association between academic success and PA after controlling for the effects of gender, employment, chronic diseases, enrollment status, and residence. Results: While increased PA linked to decreased grade point average (GPA) among off campus residents, increased PA was associated with slightly increased GPA among on-campus residents. Whereas female students had increased GPA with increased PA, male students had decreased GPA with increased PA. Conclusions: Male students and off-campus residents who engaged in more PA are more likely to have a lower GPA. Policy recommendations will help optimize student’s health outcomes and academic success.