Objective To analyze the efficacy and safety of 30% supramolecular salicylic acid combined with small-spot fractional CO2 laser in the treatment of patients with mild to moderate acne vulgaris. Methods A total of 500 patients with mild to moderate acne vulgaris admitted to the Department of Dermatology, the People's Hospital of Lincang from May 2023 to May 2024 were selected as the research subjects. According to the random number table method, they were divided into the control group (n =250) and the observation group (n =250). All patients received conventional drug treatment. On this basis, the control group was treated with 30% supramolecular salicylic acid, and the observation group was treated with 30% supramolecular salicylic acid combined with small-spot fractional CO2 laser. The treatment effect, the degree of acne and scars, quality of life and adverse reactions were compared between the two groups. Results The total effective rate of treatment in the observation group (92.80%) was higher than that in the control group (73.20%) (P <0.05). After treatment, the scores of GASS and ECCA in the two groups were lower than those before treatment, and those in the observation group were lower than those in the control group (P <0.05). After treatment, the score of DLQI in the two groups was lower than that before treatment, and that in the observation group was lower than that in the control group (P <0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P >0.05). Conclusion The application of 30% supramolecular salicylic acid combined with small-spot fractional CO2 laser in the treatment of patients with mild to moderate acne vulgaris can further improve the treatment effect, alleviate the severity of acne and facial scars,and is beneficial to improving the quality of life of patients. It will not increase the risk of adverse reactions, and has high efficacy and safety in application.