Abstract Hyperpigmentary disorders, including melasma, are challenging to treat. Glutathione has anti‐melanogenic and antioxidant properties, which led to its use as a skin‐lightening agent. Our objective was to review the published evidence and literature on the efficacy and safety of glutathione as a skin‐lightening agent and in the treatment of melasma. A literature search was done in the PubMed, Embase, and Cochrane library databases using the search terms “glutathione as a skin‐lightening agent” and “glutathione in melasma” for the past 10 years. The level of evidence, strength of recommendation, and risk of bias assessment were evaluated. Among various forms of topical glutathione, glutathione 0.5% was significantly more effective compared to glutathione 0.1% and placebo. For glutathione alone versus glutathione plus microneedling, more improvement was seen. Five randomized controlled trials and a single open‐arm clinical study on oral glutathione at doses of 250 mg once a day, 250 mg twice a day, and 500 mg once a day showed a significant reduction in the melanin index compared to placebo. The combination of topical 2% glutathione plus oral glutathione was superior to monotherapy alone. There was only one placebo‐controlled study on intravenous (IV) glutathione [6/16 (37.5%) vs. 3 (18.7%), (p0.054)]. The risk of bias assessment showed that almost an equal number of studies have low and high risk of bias. Topical versus oral glutathione both provide moderately efficacious skin‐lightening outcomes that are localized versus generalized and have minimal versus substantial adverse effects, but they are unsustainable, with variable costs. IV glutathione is contraindicated due to lack of efficacy and side effects. It may work more as an antioxidant in melasma.