BACKGROUND: Nonsuicidal self-injury (NSSI) is a major public health problem leading to psychological problems in adolescents and young adults, similar to disorders such as depression and anxiety. OBJECTIVE: The aims of this study were to investigate (1) the interaction between BMI and socioenvironmental factors (including chronotype and mental health) that contribute to NSSI, and (2) whether self-esteem plays a mediating role in this association. METHODS: From May to June 2022, the multistage cluster sampling method was used to sample college students in four grades, including freshmen and seniors. The baseline participants were followed up 6 months later, excluding those who did not qualify, and the participants included 1772 college students. Socioenvironmental factors (chronotype/mental health), self-esteem, and NSSI were measured using a questionnaire. Multivariate linear regression models and chi-square analysis were used to evaluate the linear relationship between BMI, socioenvironmental factors, and self-esteem and the NSSI status. We use a process approach (mediation-moderation analysis) to explore the complex relationships between these variables. RESULTS: The mean age of the participants was 20.53 (SD 1.65) years at baseline. A significant association was revealed, suggesting that a high BMI (β=.056, 95% CI 0.008-0.086, P=.018) was associated with a higher NSSI. There was also an interaction among BMI, socioenvironmental factors, and NSSI. Socioenvironmental factors played both moderating and mediating roles in the relationship between BMI and NSSI, whereas self-esteem only played a mediating role. CONCLUSIONS: Paying attention to factors such as overweight and obesity is important for early BMI control to identify other potential risk factors for NSSI and to evaluate how self-esteem can be improved considering multiple perspectives to improve the effect of BMI on NSSI in adolescents.