Background: Primary prevention has the potential to modify the course of depression, but the consistency and magnitude of this effect are currently undetermined. Methods: PRISMA and RIGHT compliant (PROSPERO:CRD42020179659) systematic meta-review, PubMed/Web of Science, up to June 2020. Meta-analyses of controlled interventions for the primary prevention of depressive symptoms [effect measures: standardized mean difference (SMD)] or depressive disorders [effect measure: relative risk (RR)] were carried out. Results were stratified by: (i) age range; (ii) target population (general and/or at-risk); (iii) intervention type. Quality (assessed with AMSTAR/AMSTAR-PLUS content) and credibility (graded as high/moderate/low) were assessed. USPSTF grading system was used for recommendations. Results: Forty-six meta-analyses (k=928 individual studies, n=286,429 individuals, mean age=22.4 years, 81.1% female) were included. Effect sizes were: SMD=0.08-0.53; for depressive symptoms; RR=0.90-0.28 for depressive disorders. Sensitivity analyses including only RCTs did not impact the findings. AMSTAR median=9 (IQR=8-9); AMSTAR-PLUS content median=4.25 (IQR=4-5). Credibility of the evidence was insufficient/low in 43 (93.5%) meta-analyses, moderate in two (4.3%), and high in one (2.2%): reduction of depressive symptoms using psychosocial interventions for young adults only, and a combination of psychological and educational interventions in primary care had moderate credibility; preventive administration of selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in individuals with a stroke had high credibility. Limitations: Intervention heterogeneity and lack of long-term efficacy evaluation. Conclusions: Primary preventive interventions for depression might be effective. Among them, clinicians may offer SSRIs post-stroke to prevent depressive disorders, and psychosocial interventions for children/adolescents/young adults with risk factors or during the prenatal/perinatal period.