Background: Certain personality traits have been implicated in the etiology of non-suicidal self-injury (NSSI). Sensation-seeking has predicted the number of self-harm methods tried, while impulsivity has been associated with lifetime presence of NSSI. Emotion dysregulation has been implicated in the relation between environmental (e.g., childhood trauma) and dispositional (e.g., personality traits) risk factors for engaging in NSSI. Presence of meaning in life is associated with well-being and serves as a protective factor in preserving psychological and physical health. This is the first study to date to assess whether presence of meaning moderates the relation between personality traits and engagement in NSSI. Method: Data were from adolescents at an inpatient behavioral healthcare center (N = 200, 73.7% female). Patients were primarily admitted because they were suicidal. 71% of this sample had engaged in NSSI within the past 30 days. Patients completed a survey that included measures of personality, meaning, and NSSI. Results: presence of meaning significantly moderated the relation between the personality and NSSI (p < 0.05). Conclusions: While presence of meaning was low in this sample, it did have a protective effect. This indicates that interventions that instill meaning in adolescents with mood disorders may decrease their engagement in NSSI.