Purpose: It is plausible that offspring born to mothers using tobacco during pregnancy may have increased risk of mood disorders (depression and bipolar disorders); however, mixed results have been reported. We conducted a systematic review and meta-analysis to investigate the magnitude and consistency of associations reported between prenatal tobacco use and mood disorders in offspring. Methods: We systematically searched EMBASE, SCOPUS, PubMed and Psych-INFO for studies on mood disorders and prenatal tobacco use. Methodological quality of studies was assessed with the revised Newcastle–Ottawa Scale. We estimated pooled relative risk (RR) with inverse variance weighted random-effects meta-analysis. We performed leave-one-out analyses, and stratified analyses by a subgroup (depression and bipolar disorder). Potential publication bias was assessed by inspection of the funnel plot and Egger’s test for regression asymmetry. This study protocol was prospectively registered in PROSPERO (CRD42017060037). Results: Eight cohort and two case–control studies were included in the final meta-analysis. We found an increased pooled relative risk of mood disorders in offspring exposed to maternal prenatal tobacco use RRs 1.43 (95% CI 1.27–1.60) compared to no prenatal tobacco use. Similarly, the pooled relative risks of bipolar and depressive disorders in offspring were 1.44, (95% CI 1.15–1.80) and 1.44, (95% CI 1.21–1.71), respectively. Moreover, the pooled estimated risk of mood disorders was not significantly attenuated in the studies that reported sibling comparison results [RR = 1.21 (95% CI 1.04–1.41)]. Conclusion: Taken together, there was strong evidence for a small (RR < 2) association between prenatal tobacco use and mood disorders in offspring.