Objective: This study aimed to investigate the association between the use of isotretinoin and the risk of depression in patients with acne. Design: This was a meta-analysis in which the standardized mean difference (SMD) and the relative risk (RR) were used for data synthesis employed the random-effects model. Setting: Studies were identified via electronic searches of PubMed, Embase, and the Cochrane Library up to December 28, 2017. Participants: Patients with acne. Interventions: Studies comparing isotretinoin with other interventions in patients with acne were included. Results: Twenty studies were selected. The analysis of 17 studies showed a significant association of the use of isotretinoin with improved symptoms compared with the baseline before treatment [SMD = −0.33, 95% confidence interval (CI) −0.51 to −0.15, P < 0.05; I2 = 76.6%, P < 0.05)]. Four studies were related to the analysis of the risk of depression. The pooled data indicated no association of the use of isotretinoin with the risk of depressive disorders (RR = 1.15, 95% CI 0.60–2.21, P = 0.14). The association of the use of isotretinoin with the risk of depressive disorders was statistically significant on pooling retrospective studies (RR = 1.39, 95% CI 1.05–1.84, P = 0.02), but this association was not evident on pooling prospective studies (RR = 0.85, 95% CI 0.60–2.21, P = 0.86). Conclusions: This study suggested an association of the use of isotretinoin in patients with acne with significantly improved depression symptoms. Future randomized controlled trials are needed to verify the present findings.