Justice-involved youth have high rates of psychiatric diagnoses, and these youth are often placed out-of-home, although evidence identifies several negative implications of juvenile confinement, especially for youth with psychopathology. Furthermore, youth in the justice system may be processed differently based on gender. As males and females tend to manifest symptoms differently, the psychopathology of youth may act to moderate the relationship between gender and placement in the juvenile justice system. The present study used a large, diverse sample (n = 9 851, 19.8 % female) to examine whether youth placed in various types of out-of-home facilities differed in terms of externalizing, internalizing, substance use, or comorbid disorders, and to determine the predictive value of mental health diagnoses in placement decisions. The moderation effect of psychopathology and substance use on the relationship between gender and placement also was explored. The results indicated that each type of disorder differed across placements, with internalizing being most prevalent in non-secure, and externalizing, comorbid, and substance use being most prevalent in secure settings. Mental health diagnoses improved the prediction of placement in each out-of-home placement beyond legal and demographic factors such that externalizing and substance use disorders decreased the likelihood of placement in non-secure settings, and internalizing, externalizing, and substance use disorders increased the likelihood of placement in secure and state-secure facilities. The relationship between internalizing pathology and placement in more secure facilities was moderated by externalizing pathology. The relationship between gender and placement was significantly moderated by mental health such that females with mental health diagnoses receive less secure placements. Implications for policymakers and practitioners are discussed, as well as implications for reforming juvenile justice within a developmental approach.