Background: Adolescence is a developmental stage when there is a high risk of engaging in non-suicidal self-injury (NSSI). There is recent interest in the study of thwarted belongingness and perceived burdensome as variables associated with the frequency of NSSI in adolescents. Meaning in life (MIL) could be negatively associated with thwarted belongingness and perceived burdensome. To date, no studies have analyzed whether thwarted belongingness and perceived burdensomeness could be associated with the frequency of NSSI in adolescents. On the other hand, no studies have analyzed the buffering role of MIL in the association between thwarted belongingness and perceived burdensomeness and the frequency of NSSI. Aims: a) to test whether thwarted belongingness and perceived burdensomeness are associated with NSSI frequency; b) to test whether MIL moderates the association between thwarted belongingness and NSSI frequency; and c) to test whether MIL moderates the association between perceived burdensomeness and NSSI frequency. Method: The sample consisted of N = 1531 participants between 12 and 18 years old from Spain. The participants filled out the Inventory of Statements about Self-Injury, Purpose-In-Life Test-Adolescents Version, and Interpersonal Needs Questionnaire. Moderation analysis were performed. Results: Thwarted belongingness and perceived burdensomeness were positively associated with the frequency of NSSI in Spanish adolescents. MIL was a moderating variable between thwarted belongingness and the frequency of NSSI, and between perceived burdensomeness and the frequency of NSSI. Conclusion: Thwarted belongingness and perceived burdensomeness could be a risk factor for NSSI and MIL could be a protective factor against NSSI, and adding these variables to current descriptive theories of NSSI in adolescents would allow us to improve the assessment and treatment protocols for adolescents with NSSI.