Importance: Some Black adolescents who frequently experience racial discrimination develop mental health problems. Protective caregiving may buffer adolescents from the negative mental health outcomes associated with experiencing racial discrimination., Objective: To examine if participation in programs that enhance protective caregiving will attenuate the positive association between Black adolescents' encounters with discrimination and subsequent increases in mental health problems., Design, Setting, and Participants: This secondary analysis used data from 2 randomized clinical trials testing family-centered prevention programs: the Strong African American Families-Teen (SAAF-T) program and the Adults in the Making (AIM) program. The programs were implemented in community locations convenient for participants in 12 rural Georgia counties. For the SAAF-T trial, Black adolescents and their primary caregivers were recruited from 2007 to 2008. In the AIM trial Black adolescents and their primary caregivers were recruited from 2006 to 2007. Data for this study were analyzed from June to August 2020., Exposures: Adolescents provided data at baseline on the frequency of their encounters with racial discrimination. Treatment group participants in each trial took part in a family-centered prevention program designed to prevent substance use and mental health problems. SAAF-T is a 5-session, 10-hour psychosocial intervention for families with a Black adolescent aged 14 to 16 years. AIM is a 6-session, 12-hour psychosocial intervention for families with a Black youth who is a high school senior., Main Outcomes and Measures: The primary outcomes were mental health problems, including conduct problems and depression or anxiety symptoms., Results: The SAAF-T study included 502 Black adolescents (mean [SD] age, 16.0 [0.6] years; 281 [56.0%] girls), including 252 randomized to the intervention and 250 randomized to the control, and the AIM trial included 367 Black adolescents (mean [SD] age, 17.7 [0.8] years; 217 [59.1%] girls and women), including 187 randomized to the intervention and 180 randomized to the control. Adolescents assigned to the SAAF-T intervention group who frequently experienced discrimination at baseline evinced fewer subsequent increases in conduct problems (incident risk ratio, 0.530 [95% CI, 0.340 to 0.783]). Adolescents assigned to the AIM intervention group who frequently experienced discrimination at baseline evinced fewer subsequent increases in conduct problems (mean difference, -0.361 [95% CI, -0.577 to -0.144]) and fewer subsequent increases in depression or anxiety symptoms (mean difference, -0.220 [95% CI -0.402 to -0.038]). Moderated mediation analyses suggested that enhanced protective caregiving was partially responsible for all observed interaction effects (indirect effect: SAAF-T conduct problems, -0.063 [95% CI, -0.127 to -0.001]; AIM conduct problems, -0.048 [95% CI, -0.095 to -0.001]; AIM depression or anxious symptoms, -0.036 [95% CI, -0.074 to 0])., Conclusions and Relevance: This secondary analysis of 2 randomized clinical trials found that participation in family-centered preventive interventions attenuated the association between frequent exposure to discriminatory behaviors and subsequent mental health problems. Notably, all but 1 of the treatment and moderated-mediation findings were reproduced across the SAAF-T and AIM trials., Trial Registrations: ClinicalTrials.gov Identifiers: SAAF-T, NCT04501471; AIM, NCT04510116.