First Nations children are over 17 times more likely to be removed from their families and placed in the child welfare system (CWS) than non-Indigenous children in Canada. The high rates of parent-child separation have been linked to discriminatory public services and the Indian Residential School (IRS) system, which instigated a multi-generational cycle of family disruption. However, limited empirical evidence exists linking the IRS to subsequent parent-child separations, the CWS, and mental health outcomes among First Nations, Inuit, and Métis populations in Canada. The current studies examine these relationships using a nationally representative sample of First Nations youth (ages 12–17 years) living in communities across Canada (Study 1), and among First Nations and Métis adults (ages 18+ years) in Canada (Study 2). Study 1 revealed that First Nations youth with a parent who attended IRS had increased odds of not living with either of their biological parents, and both IRS and not living with biological parents independently predicted greater psychological distress. Similarly, Study 2 revealed that First Nations and Métis adults with familial IRS history displayed greater odds of spending time in the CWS, and both IRS and CWS predicted elevated depressive symptoms. The increased distress and depressive symptoms associated with parent-child separations calls for First Nations-led interventions to address the inequities in the practices of removing Indigenous children and youth from their families.