Melasma is a chronic, relapsing hypermelanosis characterized by symmetric facial pigmentation and high recurrence rates. Natural products have been investigated for their antioxidant, anti-inflammatory, and depigmenting properties. This systematic review evaluated the efficacy and safety of natural substances for melasma treatment in randomized controlled trials, using the Melasma Area and Severity Index (MASI) as the primary outcome measure. The review was conducted in accordance with PRISMA 2020 guidelines. Searches were performed across LILACS, SciELO, Scopus, PubMed, and ScienceDirect. Randomized controlled trials investigating natural compounds for melasma treatment and reporting MASI or modified MASI (mMASI) outcomes were included. Risk of bias was assessed using the Cochrane RoB 2.0 tool. Ten randomized controlled trials met the inclusion criteria. Lycopene, hydroxytyrosol, Dorema ammoniacum , parsley, Polypodium leucotomos, pycnogenol, and Aloe vera reduced MASI/mMASI scores by 20–70%, with effects often comparable to 4% hydroquinone. Reported adverse events were generally mild, comprising transient irritation and erythema. Heterogeneity in formulations, small sample sizes, and short follow-up durations limited the overall strength of evidence. Natural compounds act through tyrosinase inhibition, antioxidant activity, and modulation of melanogenesis, constituting well-tolerated alternatives for melasma management. Larger-scale, long-term randomized trials are required to confirm sustained efficacy and safety.