Objective To evaluate the efficacy and safety of traditional Chinese medicine facial mask combined with minocycline hydrochloride capsules and fusidic acid cream in the treatment of moderate to severe acne. Methods A total of 100 patients with moderate to severe acne who received diagnosis and treatment at Dali Prefectural People's Hospital from May 2019 to January 2024 were selected, and they were divided into the control group (50 patients) and the observation group (50 patients) according to different treatment methods. The control group was treated with minocycline hydrochloride capsules combined with fusidic acid cream, and the observation group was treated with traditional Chinese medicine facial mask on the basis of the control group. The clinical efficacy, Global Acne Grading System scores and adverse reactions were compared between the two groups. Results The total effective rate of treatment in the observation group was 90.00%, which was higher than 86.00% in the control group, but the difference was not statistically significant (P >0.05). The GAGS scores in the two groups at 2, 4 and 6 weeks after treatment were lower than those before treatment, and those in the observation group were lower than those in the control group (P <0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups (P >0.05). Conclusion The combined therapy of traditional Chinese medicine facial mask, minocycline hydrochloride capsules and fusidic acid cream can not only quickly relieve the clinical symptoms of patients with moderate to severe acne and reduce the severity of acne, but also has good safety, which has high clinical application value.