Objective To analyze the efficacy and safety of fusidic acid cream combined with tretinoin cream in the treatment of adolescent acne. Methods A total of 80 adolescent acne patients admitted to our hospital from January 2024 to July 2025 were selected, and they were equally divided into group A (40 patients) and group B (40 patients) by the random number table method. Group A was treated with tretinoin cream, and group B was treated with fusidic acid cream combined with tretinoin cream. The acne severity, skin lesion severity, treatment effect and adverse reactions were compared between the two groups. Results After treatment, the scores of forehead, nose, chest, upper back, mandible, right cheek and left cheek in group B were lower than those in group A, and the differences were statistically significant (P <0.05). After treatment, the number of inflammatory and non-inflammatory lesions in group B was less than that in group A, and the difference was statistically significant (P <0.05). The total effective rate of group B (95.00%) was higher than tha t of group A (80.00%), and the difference was statistically significant (P <0.05). The incidence of adverse reactions in group B was 7.50%, which was lower than 12.50% in group A, but the difference was not statistically significant (P >0.05). Conclusion Compared with the single use of tretinoin cream, fusidic acid cream combined with tretinoin cream has a better effect in the treatment of adolescent acne. It can effectively improve the severity of acne and skin lesions, and has good safety.