BACKGROUND: Medical students face a variety of challenges during their years of medical education that can affect their quality of life (QOL). This study aimed to investigate the association of QOL with physical activity (PA), depression, and demographic characteristics, as well as to determine its predictors among medical students in different stages of education. METHODS: A cross-sectional descriptive-correlational study was conducted on 186 medical students of Tabriz University of Medical Sciences in different educational stages including basic sciences, physiopathology, externship, and internship using stratified random sampling method. Data were collected using demographic questionnaire, International PA Questionnaire, World Health Organization QOL Questionnaire, and Beck depression inventory-2. Data analysis was performed using SPSS/Ver 23 through descriptive and analytic statistics including one-way analysis of variance, independent t -test, Pearson and Spearman correlation coefficient, and multivariate linear regression model. RESULTS: There were significant differences in total score of QOL among students in different stages ( P < 0.05). There were indirect significant correlations between total score of QOL (β [confidence interval 95%]:−0.85 [−1.11–−0.59]) and its all subdomains with Beck depression score but direct significant correlations with total PA ( P < 0.05) except for social relationship. Educational stage, employment status, family income, inhabitant, moderate PA, and depression were the predictors of QOL and altogether explained 63% of its variance. CONCLUSIONS: To pay attention to the predictors of QOL, life among medical students seems necessary for increasing their QOL to provide high-quality care for people with disabilities as well as for the whole community.