Objective To analyze the effect of isotretinoin capsules+420 nm intense pulsed light on skin barrier function in patients with moderate to severe acne. Methods A total of 100 patients with moderate to severe acne treated in the Department of Dermatology, Sinopharm Tongmei General Hospital from December 2022 to December 2025 were selected. According to the random number table method, they were divided into the reference group and the observation group, with 50 patients in each group. The reference group was treated with isotretinoin capsules, and the observation group was treated with isotretinoin capsules+420 nm intense pulsed light. The clinical efffcacy, skin barrier function, Global Acne Grading System (GAGS) score and Dermatology Life Quality Index (DLQI) were compared between the two groups. Results The total effective rate of the observation group (96.00%) was higher than that of the reference group (78.00%) (P<0.05). The TEWL and erythema index in the two groups after treatment were lower than those before treatment, and those in the observation group were lower than the those in reference group (P<0.05). The epidermal water content in the two groups after treatment was higher than that before treatment, and that in the observation group was higher than that in the reference group (P<0.05). The GAGS score in the two groups after treatment was lower than that before treatment, and that in the observation group was lower than that in the reference group (P<0.05). The DLQI in the two groups after treatment was lower than that before treatment, and that in the observation group was lower than that in the reference group (P<0.05). Conclusion Isotretinoin capsules+420 nm intense pulsed light is effective in the treatment of moderate to severe acne, which can effectively improve skin barrier function, promote quality of life and relieve acne severity. It is worthy of clinical application.