Objective To study the effect of low dose isotretinoin combined with compound glycyrrhizin in the treatment of patients with severe acne. Methods A total of 100 patients with severe acne admitted to our hospital from March 2022 to March 2023 were selected as the research objects. According to the random number table method, they were divided into control group and observation group, with 50 patients in each group. The control group was treated with low-dose isotretinoin, and the observation group was treated with compound glycyrrhizin on this basis. The clinical efficacy, global acne grading system (GAGS) score, skin lesion regression time and incidence of adverse reactions were compared between the two groups. Results The total effective rate of the observation group was 94.00%, which was higher than 74.00% of the control group (P <0.05). The GAGS score and skin lesion regression time in the observation group were better than those in the control group (P <0.05). The incidence of adverse reactions in the observation group was 32.00%, which was lower than 56.00% in the control group (P <0.05). Conclusion The application of low-dose isotretinoin combined with compound glycyrrhizin can improve the clinical efficacy for patients with severe acne, reduce the GAGS score, accelerate the regression of skin lesions, and reduce the incidence of adverse reactions.