Post-traumatic stress symptoms, depressive symptoms, and psychological dysregulation have been shown to mediate the relationship between child maltreatment and non-suicidal self-injury. However, these proposed mediators often co-occur and previous research has not tested mediation when all variables are assessed simultaneously. The current study sought to advance the literature on maltreatment and self-injury by estimating the mediational effects of post-traumatic stress symptoms, depressive symptoms, and psychological dysregulation in the same multiple mediator model. Both maltreated (n = 129) and non-maltreated (n = 82) adolescent females, consisting of Caucasian (55%), African-American (37%), and Bi-racial (8%) backgrounds, participated in the study. Results indicated that only post-traumatic stress symptoms mediated the relationship between maltreatment and self-injury when all variables were included in the model. Overall, post-traumatic symptoms represented a unique pathway from maltreatment to self-injury and warrant special attention when assessing and treating such behavior with adolescent females.