Objective To compare the efficacy of minocycline hydrochloride and isotretinoin in the treatment of moderate to severe acne vulgaris. Methods A total of 60 patients with moderate to severe acne vulgaris who received treatment in the Department of Dermatology, the Fifth People's Hospital of Datong from March 2024 to March 2025 were selected and divided into the control group and the observation group by the random number table method, with 30 patients in each group. The control group was treated with oral minocycline hydrochloride capsules, and the observation group was treated with oral isotretinoin capsules. The acne symptoms, symptom improvement time and adverse reactions were compared between the two groups. Results The GAGS score of the observation group after treatment was lower than that of the control group, and the score difference before and after treatment was higher than that of the control group (P <0.05). The improvement time of comedones, inflammatory papules and pustules in the observation group after treatment was shorter than that in the control group (P <0.05). There was no significant difference in the incidence of adverse reactions between the observation group (16.67%) and the control group (13.33%) (P >0.05). Conclusion Compared with minocycline hydrochloride, isotretinoin has better efficacy in the treatment of moderate to severe acne vulgaris, with more advantages in improving symptoms and accelerating symptom relief, and does not increase the incidence of adverse reactions.