Background: Melasma is an acquired pigmentation disorder with challenges in treatment because of its refractory nature and high risk of recurrence.</p> <br></p> Objectives: This study aimed to compare the efficacy and side effects of 14 common therapies for melasma using a systematic review and network meta-analysis (NMA).</p> <br></p> Methods: The PubMed, Embase, and Cochrane Library databases were searched till December 2020 using the melasma area and severity index as a therapeutic index. A total of 59 randomized controlled trials (RCTs) met the inclusion criteria and were selected.</p> <br></p> Results: The ranking of relative efficacy compared with placebo in descending order was Q-switched Nd:Yag 1,064-nm laser (QSND), intense pulsed light, ablative fractional laser (AFL), triple combined cream (TCC), topical vitamin C, oral tranexamic acid (oTA), peeling, azelaic acid, microneedles (MNs), topical tranexamic acid (tTA), tretinoin, picosecond laser, hydroquinone (HQ), and non-AFL. Moreover, QSND was more effective than HQ and tTA against melasma. The ranking of percentage (%) of side effects in ascending order for each of 14 therapies with more than 80 participants was tretinoin (10.1%), oTA (17.6%), HQ (18.2%), AFL (20.0%), QSND (21.5%), TCC (25.7%), tTA (36.75%), peeling (38.0%), and MN (52.3%). Taking both efficacy and safety into consideration, TCC was found to be the most favorable selection among the topical drugs for melasma. QSND and AFL were still the best ways to treat melasma among photoelectric devices. oTA as system administration was a promising way recommended for melasma. Among 31 studies, 87% (27/31) studies showed that the efficacy of combination therapies is superior to that of single therapy. The quality of evidence in this study was generally high because of nearly 50% of split-face RCTs.</p> <br></p> Conclusions: Based on the published studies, this NMA indicated that QSND, AFL, TCC, and oTA would be the preferred ways to treat melasma for dermatologists. However, more attention should be paid to the efficacy and safety simultaneously during the clinical application. Most of the results were in line with those of the previous studies, but a large number of RCTs should be included for validation or update.<br></p>