Objective: To analyze the clinical therapeutic effect and aesthetic impact of non-ablative fractional CO2 laser combined with hydroquinone cream on patients with melasma. Methods: 80 patients with melasma who were admitted to the medical cosmetic dermatology department of our hospital from December 2023 to December 2025 were selected and divided into the control group and the observation group by random number table method, with 40 cases in each group. The control group was treated solely with hydroquinone cream; the observation group was intervened with non-ablative fractional CO2 laser combined with hydroquinone cream, with a treatment period of 16 weeks. The MASI score of melasma area and severity, skin melanin index, facial aesthetic VAS score, and the incidence of treatment-related adverse reactions were compared between the two groups. Results: After 16 weeks of intervention, the MASI score of the observation group was lower than that of the control group; the skin melanin index was lower than that of the control group; the facial aesthetic VAS score of the observation group was higher than that of the control group (P < 0.05); the incidence of adverse reactions between the two groups was compared (P > 0.05). Conclusion: Using non-ablative fractional CO2 laser combined with hydroquinone cream for the treatment of melasma can reduce melasma pigmentation, lower skin melanin levels, and improve the facial aesthetic appearance of patients. After standardized treatment, the incidence of adverse reactions will not significantly increase, and it is suitable for clinical selection for patients with melasma. Keywords: Melasma; Non-ablative Fractional CO2 Laser; Hydroquinone Cream; Melanocytes; Aesthetics