Melasma, a commonly acquired hyperpigmentation skin condition, is usually treated with topical agents as the first line of management. This systematic review and meta-analysis aimed to assess the efficacy and safety of azelaic acid versus hydroquinone in treating melasma patients. We conducted a comprehensive search across four online databases (PubMed, Scopus, Web of Science, and Cochrane Library) from the time of their creation until May 28, 2023. We considered randomized controlled studies comparing hydroquinone with azelaic acid for the treatment of melasma patients. We used the Cochrane Risk of Bias tool 2 to evaluate the risk of bias. The mean difference (MD) for continuous variables and the risk ratio (RR) for categorical variables, with a 95% confidence interval (CI) were pooled. Six studies were included, with a total of 673 patients with melasma. The azelaic acid had a lower mean change in melasma area severity index (MASI) than the hydroquinone group [MD= -1.23, 95% CI (-2.05, -0.40), P=0.004]. No difference was observed regarding the improvement via the objective response scale, the reduction in pigmentation, or the adverse events reported. However, despite not being statistically significantly different, there was a trend towards having more good responses in the azelaic acid group. Azelaic acid may be better than hydroquinone in reducing melasma severity (measured by MASI). However, larger studies with long-term follow-up are needed to validate these findings.