To observe the effect of fusidic acid cream combined with minocycline hydrochloride capsule in the treatment of severe acne. Methods A total of 60 patients with severe acne admitted to Tai'an No.88 Hospital from January 2020 to December 2022 were selected as the research objects. According to the random number table method, they were divided into group A and group B, with 30 patients in each group. Group A was treated with fusidic acid cream, and group B was treated with minocycline hydrochloride capsules on the basis of group A. The severity of acne (GAGS score), clinical efficacy, levels of inflammatory factors and adverse reactions were compared between the two groups. Results After 1 and 8 weeks of treatment, the GAGS score of group B was lower than that of group A (P<0.05). The total effective rate of treatment in group B was 96.67%, which was higher than 80.00% in group A (P<0.05). After treatment, the levels of INF-γ, IL-17 and IL-18 in group B were lower than those in group A (P<0.05). The incidence of adverse reactions in group B was 10.00%, which was lower than 13.33% in group A, but the difference was not statistically significant (P >0.05). Conclusion Fusidic acid cream combined with minocycline hydrochloride capsules has a good effect in the treatment of severe acne, which can effectively reduce the severity of acne in patients, and can also reduce the level of inflammatory factors. The treatment is safe and has certain clinical application value.