This study aimed to compare the efficacy and short-term tolerability of microneedling combined with either tranexamic acid or vitamin C for melasma. A systematic review and meta-analysis following PRISMA 2020 guidelines was conducted across five databases (MEDLINE, Google Scholar, EBSCO, ProQuest, Web of Science) and ClinicalTrials.gov (2015–2025). Eight studies (232 patients) were synthesized using a random-effects model; outcomes were harmonized across MASI, mMASI, and hemi-MASI using Hedges’ g calculated from within-group change-from-baseline scores, with an imputed within-person correlation (r = 0.5; sensitivity range 0.25–0.75) for split-face designs. The pooled analysis showed no statistically significant difference between tranexamic acid and vitamin C (Hedges’ g = −0.123; 95% CI, −0.311 to 0.065; P = 0.201; I2 = 0.0%). Exploratory subgroup analyses by microneedling depth, study design, and follow-up duration did not detect a significant interaction but were underpowered and should not be interpreted as confirmatory. Within the short follow-up windows reported (6–16 weeks), both interventions appeared well tolerated, with only mild and transient adverse events; long-term safety, recurrence, and delayed pigmentary complications cannot be characterized from this evidence base. A non-significant pooled difference does not establish therapeutic equivalence in the absence of a pre-specified non-inferiority margin. Microneedling with TXA and microneedling with vitamin C showed comparable short-term outcomes within this limited evidence base. Available data are compatible with a needle depth of ≤1.5 mm being adequate for transdermal delivery. Findings should be interpreted with caution given the modest sample size, predominance of split-face designs, moderate risk of bias in non-randomized studies, and limited power to detect publication bias.
