Abstract Background Melasma is a common pigmentary disorder clinically characterized by symmetric light brown to bluish-gray macules and patches with irregular, sharp borders that affect cutaneous areas, particularly the face and neck. It is commonly identified in women of reproductive ages and more commonly described in darker-skinned patients with Fitzpatrick skin types IV to VI residing in high-intensity ultraviolet radiation worldwide. It causes significant cosmetic disfigurement, psychosocial stress, and embarrassment, affecting patients’ quality of life. Objectives To evaluate the efficacy and safety of microneedling followed by tranexamic acid (TXA) cream application versus microneedling followed by tranexamic acid solution in the treatment of facial melasma. Patients and Methods This prospective split-face comparative study included thirty female patients with different types of melasma, their ages ranged from 25 to 40 years. They were recruited from the Dermatology outpatient clinic of Ain Shams University Hospitals. All patients have been treated with TXA for 3 sessions; one session every month (the right side of the face was treated by microneedling followed by TXA 5 % cream while the left side of the face was treated by microneedling followed by TXA solution 5%). Additionally, the right side of the face was treated with TXA 5% cream, and the left side applied with placebo cream twice daily for 3 months. Assessment was done by Hemi Melasma Area and Severity Index score (Hemi -MASI), patients’ satisfaction score, clinical digital photography, dermoscopic examination and area percentage of melanin concentration assessed by histopathological examination. Results Our findings showed significant improvement in different types of melasma regarding Hemi MASI score, patients’ satisfaction score, and area percentage of melanin concentration assessed by histopathological examination by Fontana-Masson stain (FM) one month after 3rd treatment session in both sides of the face. However, a minor melasma recurrence was observed two months after 3rd treatment session on both sides of the face. Meanwhile, no significant difference was observed in the treatment response of microneedling followed by TXA cream versus microneedling followed by TXA solution one month after 1st and 2nd sessions regarding Hemi MASI score, while a significant difference was observed one month after the 3rd session. Conclusion Topical TXA appears to be a promising therapeutic option in the treatment of melasma without serious adverse effects. Topical TXA cream, which was applied twice daily by the patient combined with microneedling sessions with TXA cream, has better results in comparison with microneedling sessions with TXA solution with placebo cream.