<p>Melasma is a chronic pigmentary disorder with significant therapeutic challenges. Kligman’s formula, a triple combination of hydroquinone, tretinoin, and fluocinolone acetonide, has been widely used due to its efficacy in reducing hyperpigmentation. However, its long-term effectiveness and comparative advantage over alternative treatments remain unclear. This systematic review and meta-analysis assess the efficacy and safety of Kligman’s formula in melasma treatment by analyzing changes in modified Melasma Area and Severity Index (mMASI) and Melasma Area and Severity Index (MASI) scores. A systematic search of PubMed, Google Scholar, Web of Science, Wiley, EBSCO, and OVID identified randomized controlled trials and comparative studies evaluating Kligman’s formula in melasma management. Studies reporting baseline and maintenance phase mMASI and MASI scores were included. Meta-analysis was performed using a random-effects model, and heterogeneity was assessed using the I² statistic. The pooled analysis included studies from Iran, Brazil, the USA, and India, with diverse participant characteristics. At baseline, the difference in mMASI scores between intervention and control groups was not significant (Estimate: 0.209; 95% CI −0.861 to 1.279; <i>P</i> = 0.702). At the maintenance phase, the difference in mMASI scores remained insignificant (Estimate: −0.793; 95% CI −2.535 to 0.949; <i>P</i> = 0.372), as did MASI scores (Estimate: 0.421; 95% CI −0.346 to 1.188; <i>P</i> = 0.282). Kligman’s formula does not provide a statistically significant advantage over alternative treatments in reducing melasma severity. High heterogeneity across studies suggests that genetic, environmental, and methodological factors affect outcomes. Further well-designed trials are needed to optimize melasma management and explore alternative therapies with improved efficacy and safety.</p>