Objective To investigate the clinical effect of glycolic acid combined with doxycycline in the treatment of patients with moderate to severe acne. Methods Sixty patients with moderate to severe acne admitted to Jinxiang County People's Hospital from July 2022 to June 2024 were selected as the research objects. They were divided into group control (n =30) and observation group (n =30) by random number table method. Both groups were treated with fusidic acid cream. The control group was treated with doxycycline, and the observation group was treated with glycolic acid combined with doxycycline. The clinical efficacy, severity of skin lesions, improvement of pigmentation and adverse reactions were compared between the two groups. Results The total effective rate of treatment in the observation group was 93.33%, which was higher than 70.00% in the control group, and the difference was statistically significant (P <0.05). After treatment, the GAGS score of the two groups was lower than that before treatment, and that of the observation group was lower than that of the control group, the difference was statistically significant (P <0.05). After treatment, the PAHPI score of the observation group was lower than that of the control group, and the difference was statistically significant (P <0.05). The incidence of adverse reactions in the observation group was 10.00%, which was lower than 16.67% in the control group, but the difference was not statistically significant (P >0.05). Conclusion For patients with moderate to severe acne, glycolic acid combined with doxycycline can promote the improvement of clinical efficacy, reduce the severity of skin lesions and pigmentation, and will not increase the risk of adverse reactions, which is worthy of clinical application.