Introduction: Physical activity (PA) significantly impacts mental health. However, studies addressing the influence of PA on the mental health and academic performance of medical students are scarce.Materials and methods: A cross-sectional study was carried out among 2,819 students pursuing their medical degrees in Saudi Arabia. PA was measured using the Global Physical Activity Questionnaire, and the state of their mental health was recorded using the Hospital Anxiety and Depression Scale. A multi-logistic regression was performed to predict the risk factor of poor academic performance.Results: The prevalence of abnormal anxiety and depression levels were found to be 45.3% and 31.6%, respectively, which were comparatively more prevalent among students of younger age (p < 0.001). Students with abnormal anxiety levels had significantly lower grade point average (GPA) levels than others (p < 0.001). Those who were aged < 21 years, female gender, with chronic disease presence, low PA levels, and abnormal anxiety levels were independently associated with lower GPA levels (p < 0.05).Conclusion: Low PA and high anxiety and depression levels were found to affect the academic performance of medical students in Saudi Arabia. Hence, health education about the importance of PA should be directed to those students.