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Background: The evidence available on the association between social support and prevention of depression has been basically obtained from observational studies. Aim: We evaluated the effectiveness of social support-based interventions for the prevention of depression in people without clinical depression. Methods: Systematic review and meta-analysis (SR/MA) of randomized controlled trials (RCT), which were searched for in MEDLINE, EMBASE, CENTRAL, WOS, PsycINFO, OpenGrey and other sources from the inception dates to June 8, 2022. We selected RCTs that assessed the effectiveness of social support-based interventions as compared to controls, included subjects without baseline clinical depression, and measured as results a reduction in depressive symptoms and/or the incidence of new cases of depression. Pooled standardized mean differences (SMDs) were calculated from random effects models. Results: Nine RCTs involving 927 patients from North America, Asia and Europe were included. The pooled SMD was −0.43 [95% confidence interval (CI) −0.82 to −0.04; p =.031]. Sensitivity analyses confirmed the robustness of results. Heterogeneity was substantial [ I 2 = 80% (95% CI: 64% to 89%)]. A meta-regression model that included usual care as comparator and the continent (Europe), explained 53% of heterogeneity. Eight RCTs had a moderate overall risk of bias and one had a high risk of bias. Follow-up was ⩾1 year in only three RCTs. There was no statistical evidence of publication bias. The quality of evidence, as measured on GRADE guidelines, was low. Conclusion: Social support-based interventions had a small preventive effect on depression. Longer RCTs with a low risk of bias are necessary. [ABSTRACT FROM AUTHOR]