Maternal depression is a well-established risk factor for the development of depression in offspring. As such, reducing maternal depression may be key to effective prevention efforts to reduce offspring's depression. Based on the broad risk represented by maternal depression, examining cross-over effects of parent-focused interventions on maternal depression is important. The present study examined improvements in maternal depression as a mediator of the long-term effects of the Family Check-Up (FCU) prevention program on youth depression across three randomized controlled trials. The FCU is a family-focused intervention originally designed to reduce youth problem behaviors, particularly conduct problems and substance use, but has also been found to have cross-over effects on other youth problem behaviors, including internalizing symptoms. We utilized integrative data analysis that allows for powerful tests of prevention effects across trials, specifically moderated nonlinear factor analysis, to integrate data across three trials: one trial initiated in early childhood and two in early adolescence. Using a latent growth modeling approach, we first examined direct effects of the FCU on changes in maternal depression. Then we examined the mediating effect of maternal depression on changes in both parent and youth reports of youth depression. A significant intervention effect on maternal depression was observed across the three trials, with the FCU predicting improvements in maternal depression. In turn, such improvements predicted a reduction in the growth in both parent and youth reports of youth depressive symptoms across 10 years post baseline. These results demonstrate the utility in addressing cross-over effects of family-focused interventions in reducing the long-term development of depression in youth through mediating pathways.