BackgroundAdult substance use contributes to high rates of child maltreatment, adverse parenting, and poor child well-being outcomes. The Children’s Bureau in the Administration for Children and Families, U.S. Department of Health and Human Services funded the Regional Partnership Grant (RPG) program to improve safety, well-being, and permanency outcomes for children at risk of or in out-of-home placements because of caregivers’ substance use. ObjectiveThis study estimates the effect of the RPG program on adult parenting and recovery outcomes, as well as child safety, permanency, and well-being outcomes. Participants and settingThis study included samples from three RPG projects funded in 2014. A total of 437 families were included in the evaluation: 198 enrolled in RPG and 239 in the comparison group. MethodsOutcomes included both administrative data and standardized instruments collected at program entry and exit. Impacts were calculated by comparing regression-adjusted differences between RPG participants and a well-matched comparison group. ResultsThe RPG program showed two favorable and statistically significant impacts on adult outcomes: reduced trauma symptoms (ES = −0.25, p = 0.02), and depressive symptoms (ES = −0.25, p = 0.03). In addition, children enrolled in RPG had reduced behavior problems (ES = −0.31, p = 0.02) and reduced executive functioning deficits (ES = −0.31, p = 0.04). There were no significant impacts observed for child safety and permanency outcomes. ConclusionsThe RPG approach has produced several favorable impacts on key mental health needs of caregivers and children, establishing foundational evidence of program effectiveness. Additional evaluation research is necessary to understand the effectiveness on additional outcomes with a larger, more generalizable sample.