Background Melasma is a hyperpigmentation disorder in the form of a light brown to blackish macula with irregular edges that are often exposed to sunlight, especially the face. The causes of melasma are still not widely understood and the treatment remains a challenge. Topical cysteamine recently has been studied as a promising depigmenting agent in treating melasma. This study aimed to compare the effectiveness of cysteamine cream in treating melasma towards mainstay therapy, hydroquinone (HQ). Methods Online searching on Pubmed-MEDLINE, Scopus, EBSCOhost, ProQuest, and Cochrane Library databases found 3 relevant articles included in this systematic review and meta-analysis (n=128). The outcome measured was mMASI and MELASQoL scores. Results The meta-analysis showed a reduction in mMASI score by week 8 (SMD=0.33(95% CI - 0.02 - 0.68), p=0.92, I2=0%) and week 16 (SMD=0.13(95% CI -0.02 - 0.48), p=0.89, I2=0%) in both cysteamine and control groups. The meta-analysis also demonstrated a reduction in MELASQoL score (SMD=0.23(95% CI -0.16 - 0.62), p=0.16, I2=50%) compared with baseline. Conclusion Results revealed that both 5% cysteamine and 4% HQ cream had similar favorable efficacy in treating melasma and also increasing melasma patient’s quality of life . © 2023 Pakistan Association of Dermatologists. All rights reserved.