Objective To explore the effect of new supramolecular salicylic acid combined with Liangxue Qingfei powder in the treatment of patients with moderate to severe acne on their inflammatory factor levels. Methods A total of 84 patients with moderate to severe acne admitted to our hospital from April 2022 to September 2023 were selected as the research subjects. According to different treatment plans, they were divided into the control group and the observation group, with 42 patients in each group. The control group received new supramolecular salicylic acid treatment, and the observation group received new supramolecular salicylic acid combined with Liangxue Qingfei powder treatment. The inflammatory factor levels, acne severity, quality of life, treatment effect and adverse reactions were compared between the two groups. Results After treatment, the levels of IL-4, IL-8 and TNF-α in the observation group were lower than those in the control group (P <0.05). After treatment, the score of GAGS in the observation group was lower than that in the control group (P <0.05). After treatment, the score of DLQI in the observation group was lower than that in the control group (P <0.05). The total effective rate of treatment in the observation group (92.86%) was higher than that in the control group (71.43%) (P <0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P >0.05). Conclusion The combination of new supramolecular salicylic acid and Liangxue Qingfei powder in the treatment of moderate to severe acne shows good efficacy. It can effectively reduce the levels of inflammatory factors, alleviate the severity of acne, which is beneficial to improving the quality of life of patients. Moreover, it does not increase the risk of adverse reactions, with higher application safety.