Background: Stubborn dyschromia such as melasma and post-inflammatory hyperpigmentation (PIH) are leading causes for cosmetic consultation. Topical treatment is challenging, using a range of modalities, to stop, hinder, and/or prevent steps in the pigment production process. Tranexamic acid (TXA), a potent plasmin inhibitor, is proposed to control pigmentation by inhibiting the release of inflammatory mediators involved in triggering melanogenesis. TXA has been recently introduced as a topical therapy aimed at reducing pigmentation in melasma. Methods: In a 12-week clinical study, a novel, topical facial serum containing 3% TXA, 1% kojic acid, and 5% niacinamide was evaluated for its effectiveness in treating melasma, PIH, and hyperpigmentation in Brazilian female subjects with Fitzpatrick skin types I-IV. Efficacy evaluations were performed at pre-treatment baseline, weeks 2, 4, 8, and 12, and included expert clinical grading, bio-instrumental measurements, and self-assessment questionnaires. Cutaneous tolerability was also evaluated by assessing subjective and objective irritation of the treatment area. Results: A significant improvement in the appearance of PIH, hyperpigmentation, melasma, skin texture, and skin tone homogeneity was observed beginning at week 2 and continued through week 12. Melanin index, as measured by Mexameter®, demonstrated a significant decrease by week 12 as compared to both pre-treatment baseline and control. Conclusions: The findings suggest that the test product is an effective and well-tolerated treatment option for addressing hyperpigmentary conditions, including melasma. Additional in vitro data suggests that TXA may act by mediating the inhibition of PGE2-stimulated human epidermal melanocytes. J Drugs Dermatol. 2019;18(5):454-459.