BackgroundPrevious studies have suggested a significant association between mobile phone addiction (MPA) and non-suicidal self-injury (NSSI) in general adolescents. However, limited research has analyzed this relationship in clinical populations, such as those with major depressive disorder (MDD), and the potential mediation mechanisms remain unclear.MethodsThis cross-sectional observational study analyzed data from 2343 adolescents with MDD (77.9% females; mean age = 14.99 years, SD = 1.65). Using mediation models, we explored the roles of self-esteem and depression severity (measured by Patient Health Questionnaire-9) in the relationship between MPA and NSSI. Additionally, we evaluated the associations between existing school-implemented mobile phone usage policies and levels of MPA, self-esteem, depression symptoms, and NSSI.ResultsMPA was significantly associated with NSSI, with low self-esteem and increased depression severity almost entirely mediating this effect (log-odds = 0.016, 95%CI = 0.02–0.013). Subdomains of MPA, including inability to control craving, feelings of anxiety, and productivity loss, followed similar mediation models, while the subdomain of withdrawal/escape had a partial effect mediated by depression severity. Additionally, enforced restrictions on mobile phone usage in schools did not show positive effects on related variables and even exacerbated MPA by increasing cravings and reducing productivity.ConclusionOur study suggests that MPA in adolescents with MDD may be an important risk factor for NSSI occurrence, and that reducing the negative impact of mobile phone usage on self-esteem and depressive symptoms, rather than simply restricting usage, may be crucial for effective intervention.