Context: Saffron (Crocus sativus L.) has gained interest as a potential treatment in psychiatry. Objective: This systematic review and meta-analysis sought to investigate the effect of saffron supplementation, as both an adjunctive therapy and monotherapy, on symptoms of depression and anxiety in clinical and general populations compared with pharmacotherapy or placebo. Data sources: Using the PRISMA guidelines, a systematic literature review of randomized controlled trials was conducted. Data extraction: A meta-analysis was conducted to determine treatment effect. Risk of bias was assessed using the Jadad scale. Results: Twenty-three studies were included. Saffron had a large positive effect size when compared with placebo for depressive symptoms (g = 0.99, P < 0.001) and anxiety symptoms (g = 0.95, P < 0.006). Saffron also had a large positive effect size when used as an adjunct to antidepressants for depressive symptoms (g = 1.23, P = 0.028). Egger's regression test found evidence of publication bias. Conclusions: Saffron could be an effective intervention for symptoms of depression and anxiety; however, due to evidence of publication bias and lack of regional diversity, further trials are required. PROSPERO registration CRD42017070060.