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) might be negatively associated with thwarted belongingness and perceived burdensomeness. To date, no studies have analyzed the buffering role of MIL in the association between thwarted belongingness and perceived burdensomeness and the frequency of lifetime NSSI in Spanish adolescents. Aims: (a) To test whether thwarted belongingness and perceived burdensomeness are associated with frequency of lifetime NSSI; (b) to test whether MIL moderates the association between thwarted belongingness and frequency of lifetime NSSI; and (c) to test whether MIL moderates the association between perceived burdensomeness and frequency of lifetime NSSI. Method: The sample consisted of N = 1531 participants (n = 736, 48.1%, were men, and n = 795, 51.9%, were women) between 12 and 18 years old from Spain. The participants filled out the Inventory of Statements about Self-Injury, Purpose-In-Life Test-Adolescent Version, and Interpersonal Needs Questionnaire. Moderation analyses were performed. Results: No statistically significant differences were found in the frequency of lifetime NSSI in the adolescents based on gender. Thwarted belongingness and perceived burdensomeness were positively associated with the frequency of lifetime NSSI in Spanish adolescents. MIL was a moderating variable between thwarted belongingness and the frequency of lifetime NSSI, and between perceived burdensomeness and the frequency of lifetime NSSI. Conclusions: Thwarted belongingness and perceived burdensomeness might be positively associated with the frequency of lifetime NSSI, and MIL might be negatively associated with the frequency of lifetime NSSI. Thus, adding these variables to current descriptive theories of NSSI in adolescents would allow us to improve assessment and treatment protocols for adolescents with NSSI. Keywords: Spanish adolescents; meaning in life; non-suicidal self-injuries; perceived burdensomeness; thwarted belongingness.