Children with parents suffering from a psychiatric disorder are at higher risk for developing a mental disorder themselves. This systematic review and meta-analysis of randomized controlled trials aims to evaluate the efficacy of psychosocial interventions to prevent negative mental health outcomes in the offspring of parents with mental illness. Eight electronic databases, grey literature and a journal hand-search identified 14 095 randomized controlled trials with no backward limit to June 2021. Outcomes in children included incidence of mental disorders (same or different from parental ones) and internalizing and externalizing symptoms at post-test, short-term and long-term follow-up. Relative risks and standardized mean differences (SMD) for symptom severity were generated using random-effect meta-analyses. Twenty trials were selected (pooled n = 2689 children). The main therapeutic approaches found were cognitive-behavioural therapy and psychoeducation. A significant effect of interventions on the incidence of mental disorders in children was found with a risk reduction of almost 50% [combined relative risk = 0.53, 95% confidence interval (CI) 0.34–0.84]. Interventions also had a small but significant effect on internalizing symptoms at post-test (SMD = −0.25, 95% CI −0.37 to −0.14) and short-term follow-up (−0.20, 95% CI −0.37 to −0.03). For externalizing symptoms, a decreasing slope was observed at post-test follow-up, without reaching the significance level (−0.11, 95% CI −0.27 to 0.04). Preventive interventions targeting the offspring of parents with mental disorders showed not only a significant reduction of the incidence of mental illness in children, but also a diminution of internalizing symptoms in the year following the intervention.