Background: Research has demonstrated that parent-child attachment security and school connectedness (SC) are protective factors against substance use, depression, and suicidality during adolescence. However, past research has examined these factors independently, and little is known about how attachment security and SC work in conjunction to reduce risk. Objective: The present study examined the moderating role of SC on the relations between parent-adolescent attachment (security, anxiety, and avoidance) and substance use, depression, and suicidality among at-risk adolescents. Method: Using a cross-sectional design, 480 community-based adolescents (60.5% female; M[subscript age] = 14.86) aged 12-18 years self-reported parent-adolescent attachment, adolescent substance use, depression, and suicidality. Results: High levels of attachment security in conjunction with high SC predicted the lowest risk for adolescent substance use. Several sex differences were found: SC significantly moderated the relation between attachment security and depressive symptoms in female adolescents and suicidality in male adolescents. Results also revealed that the moderating of role of SC differed in relation to attachment anxiety versus attachment avoidance for female versus male adolescents. Conclusion: Findings point to the importance of testing associations between multiple dimensions of attachment and SC on several well-established mental health outcomes in a sample of high-risk adolescents.