Background Melasma is a common, multifactorial, and recurring disease which is not easy to treat. Aims The purpose of this study is to evaluate the efficacy of microneedling in combination with Q-switched neodymium-doped yttrium aluminum garnet laser (QsNd-YAG laser) for treatment of melasma. Patients/Methods Fifteen female patients with epidermal or mixed-type melasma on the face were included in the study. Patients were first treated with QsNd-YAG laser, and then with microneedling containing mesotherapy products of biomimetic peptides, at the same session. Modified Melasma Area Severity Index (mMASI) scores were calculated before the first session and again 2 weeks after the last session. The same treatment protocol was repeated every 2 weeks for five sessions within period of 3 months of therapy. The evaluation was performed according to the before and after photographs taken from three angles including 90-degree front and 45 degrees from left and right with the VISIA device. Results Of the 15 patients included in the study, the mean mMASI scores before and after treatment were 9.2 +/- 5.7 (3.8-23.1) and 3.6 +/- 4.0 (0.6-16.8), respectively. mMASI scores were significantly reduced after completion of the protocol. Six (40%) patients had "very good response," 4 (26.7%) patients had "good response," and 5 (33.3%) patients were "unresponsive." Six (40%) patients were followed up for 1 year, and only 1 patient had a recurrence (6.7%). Conclusions In addition to the use of photoprotective measures, multimodality treatment including QsNd-YAG laser and microneedling with mesotherapy products containing biomimetic peptides is effective to treat melasma and they work synergistically.