Families exposed to maltreatment have high rates of co-occurring substance misuse. Yet, few child welfare interventions concurrently address both child maltreatment and parental substance misuse and, therefore, fail to intervene around their shared precipitants. Mindfulness is one approach that shows promise in cultivating awareness and self-regulation skills, which may in turn promote healthy family functioning. This pilot study used a randomized controlled trial (RCT) to test the initial efficacy of a six-session mindfulness-informed intervention on proximal (parenting stress, heart rate variability, coping, and mindfulness) and distal (parental substance misuse, child maltreatment potential, and child behavior) domains of family functioning. Participants included 28 child welfare-involved parents with children (birth-16 years) randomized to the mindfulness-informed intervention or wait-list control group. Intention-to-treat (ITT) analyses were conducted on the entire randomized sample for all self-report outcome measures, and repeated measures ANOVAs were conducted as secondary analyses on the per protocol sample (N = 21) for heart rate variability. ITT analyses indicated significant group by time differences, with intervention participants demonstrating reductions in parenting stress (p < 0.05, Cohen’s d = 0.98), child abuse potential (p < 0.05, Cohen’s d = 1.03), and child behavior problems (p < 0.001, Cohen’s d = 3.28), and improvements in mindfulness awareness (p < 0.01, Cohen’s d = 1.37) and non-judgment (p < 0.05, Cohen’s d = 1.21) compared to the control group from pre- to post-assessment. In addition, repeated measures ANOVAs indicated significant group by time differences on participant heart rate variability from pre- to post-assessment (p < 0.01, Cohen’s d = 1.67). Future directions for child welfare practice and intervention development and testing are discussed.