Objective To explore the effect of isotretinoin capsules+fusidic acid cream in the treatment of patients with moderate-to-severe acne vulgaris. Methods A total of 120 patients with moderate-to-severe acne vulgaris admitted to the Central Hospital of Xiangtan from January 2023 to December 2024 were selected, and they were divided into the control group and the observation group by the random number table method, with 60 patients in each group. The control group was treated with isotretinoin capsules, and the observation group was treated with isotretinoin capsules+fusidic acid cream. The acne severity, clinical efficacy, number of skin lesions and adverse reaction rate were compared between the two groups. Results 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 control group (P <0.05). The total effective rate of treatment in the observation group (96.67%) was higher than that in the control group (86.67%) (P <0.05). The number of inflammatory, non-inflammatory and total lesions in the two groups after treatment was lower than that before treatment, and that in the observation group was lower than that in the control group (P <0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P >0.05). Conclusion The overall efficacy of isotretinoin capsules+fusidic acid cream in patients with moderate-to-severe acne vulgaris is excellent. It can reduce lesions and relieve symptoms, without increasing the incidence of adverse reactions, and the safety is also guaranteed.