This study aimed to investigate the mediating effect of self-esteem on the relationship between home-based physical activity and the general well-being of university students. A web-based questionnaire survey was conducted on 311 Chinese university students using the Physical Activity Rating Scale, Rosenberg Self-Esteem Scale, and General Well-Being Scale. The influence of home-based physical activity on self-esteem and general well-being in Chinese university students was explored using a one-way ANOVA analysis of variance. The mediating model was tested with regression analysis to determine the mediating effects of self-esteem between home-based physical activity and general well-being among Chinese university students during COVID-19. The amount of home-based physical activity had a significant effect on the general well-being (F= 3.46,P< 0.05) and self-esteem (F= 6.99,P< 0.01) of university students. The study found that self-esteem had a full mediation (T= 4.445,P< 0.001) between medium and large amounts of home-based physical activity and general well-being among university students, accounting for 32.5% of the total effect. The study concluded that self-esteem mediated the relationship between home-based physical activity and general well-being in university students during the COVID-19 pandemic. The findings in this study highlight the importance of home-based physical activity in increasing the general well-being of university students during the pandemic.