Previous research indicates that sensation seeking, emotion dysregulation, and impulsivity are predictive of non-suicidal self-injury (NSSI). A body of research supports that meaning in life predicts improved mental health and well-being, including fewer suicidal thoughts and attempts, yet no research has examined the moderating effects of meaning in life on the relations between personality and temperament and NSSI. Given the growing incidence rates of NSSI among adolescents and the potential lifelong consequences of NSSI, it is imperative to better understand the factors that reduce the rates at which adolescents in a clinical sample engage in NSSI. The present study investigates if the protective factors of meaning in life moderate the relation between personality and temperament variables and NSSI among 126 adolescents (71% female, Mage = 16.1, SD = 1.1, range 13–18, 80% White) residing in an inpatient psychiatric hospital who endorsed NSSI in the last 12 months. Results from hurdle modeling indicate that two subtypes of meaning in life, presence of meaning in life and search for meaning of life, may serve as robust protective factors against engagement in NSSI among a clinical sample of adolescents. Additionally, results suggest that search for meaning, but not presence of meaning in life, variables moderate the relations between personality and temperament and NSSI. Results provide evidence that meaning in life is an understudied variable of importance in understanding how to prevent or treat NSSI. It also underscores the need to develop, refine, and test meaning-making interventions.