Objective To explore the effect of carbon dioxide fractional laser combined with supramolecular salicylic acid on skin barrier function in patients with moderate to severe facial acne. Methods A total of 82 patients with moderate to severe facial acne admitted to our hospital from January 2023 to April 2025 were selected, and they were divided into the reference group and the observation group by the random number table method, with 41 patients in each group. The reference group was treated with supramolecular salicylic acid alone, and the observation group was treated with carbon dioxide fractional laser combined with supramolecular salicylic acid. The skin barrier function, skin status, prognosis time and clinical efficacy were compared between the two groups. Results After treatment, the transepidermal water loss, erythema value, melanin value, pH value and stratum corneum hydration of the observation group were better than those of the reference group (P <0.05). After treatment, the measured values of erythema, pores and porphyrin in the observation group were lower than those in the reference group, and the time of initial crusting and crust shedding was shorter than that of the reference group (P <0.05). The total effective rate of treatment in the observation group (95.12%) was higher than that in the reference group (73.17%) (P <0.05). Conclusion Carbon dioxide fractional laser combined with supramolecular salicylic acid in the treatment of patients with moderate to severe facial acne can improve their skin barrier function, enhance skin status, shorten crusting time and crust shedding time, and improve treatment effectiveness.