Objective: To evaluate the efficacy of 755-nm picosecond alexandrite laser with nanomicroneedle-assisted transdermal glutathione delivery in melasma.Methods:80 melasma patients treated at Nanjing Huahan Qizhi Aesthetic Hospital from Jan 2022 to Aug 2025 were enrolled and grouped by treatment regimen. Control group (n=40) received 755-nm picosecond laser monotherapy; observation group (n=40) received additional nanomicroneedle-assisted glutathione delivery. The modified Melasma Area and Severity Index (mMASI), skin barrier parameters (stratum corneum hydration, sebum, transepidermal water loss [TEWL], pH), overall response rate, and adverse events were compared.Results: Baseline indices showed no significant intergroup difference (P>0.05). At 3-month post-treatment follow-up, the observation group had a lower mMASI score (P<0.05), higher stratum corneum hydration and sebum but lower TEWL and pH (P<0.05), and a higher overall response rate (P<0.05). No significant difference was found in adverse event incidence between the two groups (P>0.05).Conclusions: The combination of 755-nm picosecond laser and nanomicroneedle-assisted glutathione delivery can mitigate the severity of melasma, promote the restoration of skin barrier function, and demonstrates a favorable safety profile, holding value for clinical promotion.