Objective To analyze the clinical effect of supramolecular salicylic acid combined with photonrejuvenation in the treatment of acne vulgaris. Methods A total of 60 patients with acne vulgaris admitted to our hospital from January 2022 to January 2023 were randomly divided into control group and experimental group, with 30 patients in each group. The control group was treated with single photonrejuvenation, and the experimental group was treated with supramolecular salicylic acid combined with photonrejuvenation. The therapeutic effect, skin damage, adverse reactions, psychological status and quality of life were compared between the two groups. Results The total effective rate of treatment in the experimental group was 96.67%, which was higher than 70.00% in the control group (P <0.05). The scores of skin acne, papules, abscesses, cysts and nodules, and skin color in the experimental group were lower than those in the control group (P <0.05). The incidence of adverse reactions in the experimental group was lower than that in the control group, but the difference was not statistically significant (P >0.05). After treatment, the SAS score and SDS score of the experimental group were lower than those of the control group (P <0.05). The scores of each dimension of quality of life in the experimental group were higher than those in the control group (P <0.05). Conclusion Supramolecular salicylic acid combined with photorejuvenation is effective in the treatment of acne vulgaris, which can effectively improve skin damage, reduce skin pain, relieve adverse psychological emotions, improve quality of life, and has high safety.