Background: Melasma remains a therapeutically challenging hyperpigmentation disorder due to its high recurrence rate and the limitations of existing topical therapies. Nicotinamide adenine dinucleotide (NAD(+)) is a fundamental coenzyme critical for mitochondrial bioenergetics, DNA repair, and NAD(+)-dependent sirtuin-mediated gene regulation. Its systemic decline is implicated in cellular ageing and dysfunction. This study examines a novel procedural intervention, which involves the intradermal delivery of high-dose NAD(+) utilizing a microneedling therapy system (MTS). Objectives: To evaluate the efficacy and safety of a series of microneedling sessions followed by topical sterile NAD(+) booster application at three-week intervals for melasma management. Methods: A prospective single-centre case series was conducted over 21 weeks involving 36 Korean female patients with mixed-type melasma. Participants received five treatment sessions consisting of MTS immediately followed by NAD(+) (Sihler N, Sihler Inc., Korea). The primary outcome measure was the change in Melasma Area and Severity Index (MASI) score from baseline to week 21. Secondary outcomes included blinded photographic evaluation using a 5-point Global Aesthetic Improvement Scale (GAIS) and patient-reported satisfaction measures. Results: All enrolled participants completed the treatment protocol. Analysis revealed a statistically significant reduction in mean MASI score from 16.8 +/- 5.2 at baseline to 6.9 +/- 3.1 at week 21 (p < 0.001), representing a 59.2% improvement. Independent blinded dermatological assessment rated 83.3% of patients as demonstrating clinical improvement. The procedure demonstrated an excellent safety profile with only transient erythema and oedema observed, resolving spontaneously within 48 hours. Conclusions: The combination of MTS with microneedling-assisted topical application of sterile NAD(+) appears to be an effective and well-tolerated intervention for melasma management. The distinct mechanism of action, focused on supporting cellular function, warrants further investigation in randomized controlled designs (e.g. split-face or vehicle-controlled trials). Level of evidence iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .