Abstract Objective The study aims to examine how moderate-to-vigorous physical activity (MVPA) affects the severity of depression symptoms among Chinese college students. Additionally, it seeks to analyze the mediating mechanisms involving self-rated health and general self-efficacy. Methods The study utilized data from the 2023 Chinese College Health Tracking Survey and employed multiple linear regression and structural equation modeling techniques to investigate the impacts of MVPA on depression levels and its underlying mediating mechanisms among college students. The primary cohort comprised 49,717 enrolled college students from 106 universities in China. Results A total of 41,620 valid questionnaires were collected (response rate: 83.7%), with females accounting for 58.6%. In the past month, approximately 30.2% of college students engaged in MVPA. Self-rated health (B = − 0.282, P