Objective To investigate the effect of topical 5-aminolevulinic acid photodynamic therapy on inflammatory factors and skin lesions in patients with moderate to severe acne. Methods A total of 50 patients with moderate to severe acne admitted to Qingyuan Chronic Disease Prevention and Treatment Hospital from December 2022 to December 2023 were selected as the research subjects. According to the random number table method, they were divided into the control group and the study group, with 25 patients in each group. The control group was treated with red and blue light irradiation, and the study group was treated with topical 5-aminolevulinic acid photodynamic therapy. The skin lesions, inflammatory factor levels, clinical efficacy and recurrence rate were compared between the two groups. Results The number of inflammatory and non-inflammatory skin lesions in the study group was less than that in the control group (P <0.05). The levels of IL-8, TNF-α and CRP in the study group were lower than those in the control group (P <0.05). The total effective rate of treatment in the study group (96.00%) was higher than that in the control group (76.00%) (P <0.05). The recurrence rates at 1, 3, and 6 months after treatment in the study group were lower than those in the control group (P <0.05). Conclusion Topical 5-aminolevulinic acid photodynamic therapy for moderate to severe acne can reduce the number of skin lesions and lower the levels of inflammatory factors, with definite effect and low recurrence rate, which is worthy of clinical application.