Objective To compare the effects of minocycline hydrochloride and isotretinoin in the treatment of patients with moderate to severe acne vulgaris. Methods A total of 240 patients with moderate to severe acne vulgaris admitted to Beijing Armed Police Corps Hospital from February 2022 to February 2025 were selected. According to the random number table method, they were divided into the reference group and the study group, with 120 patients in each group. The reference group was treated with minocycline hydrochloride, and the study group was treated with isotretinoin. The treatment effect, adverse reaction rate, symptom improvement time, Global Acne Grading System (GAGS) score and recurrence rate were compared between the two groups. Results The total effective rate of the study group (99.17%) was higher than that of the reference group (93.33%) (P<0.05). The incidence of adverse reactions in the study group was lower than that in the reference group, but the difference was not statistically signiffcant (P>0.05). The inffammatory papule improvement time, comedone improvement time and pustule improvement time in the study group were shorter than those in the reference group (P<0.05). After treatment, the GAGS score of the study group was lower than that of the reference group (P<0.05). The recurrence rate of the study group was 0.83%, which was lower than 6.67% of the reference group (P<0.05). Conclusion Isotretinoin has a better treatment effect than minocycline hydrochloride in the treatment of moderate to severe acne vulgaris, with higher efffcacy and safety. It can rapidly improve the clinical symptoms of patients and help to reduce the disease recurrence rate.