This umbrella review searches PubMed, Scopus, and PsycINFO to summarize and grade the strength of evidence of the associations between antidepressants and adverse outcomes reported in multiple meta-analyses. Importance Antidepressant use is increasing worldwide. Yet, contrasting evidence on the safety of antidepressants is available from meta-analyses, and the credibility of these findings has not been quantified. Objective To grade the evidence from published meta-analyses of observational studies that assessed the association between antidepressant use or exposure and adverse health outcomes. Data Sources PubMed, Scopus, and PsycINFO were searched from database inception to April 5, 2019. Evidence Review Only meta-analyses of observational studies with a cohort or case-control study design were eligible. Two independent reviewers recorded the data and assessed the methodological quality of the included meta-analyses. Evidence of association was ranked according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. Results Forty-five meta-analyses (17.9%) from 4471 studies identified and 252 full-text articles scrutinized were selected that described 120 associations, including data from 1012 individual effect size estimates. Seventy-four (61.7%) of the 120 associations were nominally statistically significant at P <= .05 using random-effects models. Fifty-two associations (43.4%) had large heterogeneity (I-2 > 50%), whereas small-study effects were found for 17 associations (14.2%) and excess significance bias was found for 9 associations (7.5%). Convincing evidence emerged from both main and sensitivity analyses for the association between antidepressant use and risk of suicide attempt or completion among children and adolescents, autism spectrum disorders with antidepressant exposure before and during pregnancy, preterm birth, and low Apgar scores. None of these associations remained supported by convincing evidence after sensitivity analysis, which adjusted for confounding by indication. Conclusions and Relevance This study's findings suggest that most putative adverse health outcomes associated with antidepressant use may not be supported by convincing evidence, and confounding by indication may alter the few associations with convincing evidence. Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases. No absolute contraindication to antidepressants emerged from this umbrella review. Question Is antidepressant use associated with adverse health outcomes, and how credible is the evidence behind this association in published meta-analyses of real-world data? Findings In this systematic umbrella review of 45 meta-analyses of observational studies, convincing evidence was found for the associations between antidepressant use and suicide attempt or completion among individuals younger than 19 years and between antidepressant use and autism risk among the offspring. However, none of these associations remained at the convincing evidence level after a sensitivity analysis that adjusted for confounding by indication. Meaning This study's findings suggest that claimed adverse health outcomes associated with antidepressants may not be supported by strong evidence and may be exaggerated by confounding by indication; no absolute contraindication to the use of antidepressants was found to be currently supported by convincing evidence.