Objective To explore the clinical effect of photodynamic therapy combined with Xiaocuo ointment in the treatment of moderate to severe acne (MSA) and its influence on the skin barrier function. Methods A total of 60 patients with MSA who were diagnosed and treated in our hospital from October 2020 to August 2024 were selected as the research subjects. According to the random number table method, they were divided into the control group (n =30) and the observation group (n =30). The control group received photodynamic therapy, and the observation group received photodynamic therapy combined with Xiaocuo ointment. The clinical effect, skin barrier function, skin lesion and adverse reaction rate were compared between the two groups. Results The total treatment effective rate in the observation group (90.00%) was higher than that in the control group (66.67%) (P <0.05). After treatment, the SCH in the observation group was higher than that in the control group, and the TEWL, pH value and skin oil content in the observation group were all lower than those in the control group (P <0.05). The skin lesion scores in the two groups at 1 week, 2 weeks, 3 weeks and 3 months after treatment were lower than those before treatment, and the scores in the observation group were lower than those 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 Photodynamic therapy combined with Xiaocuo ointment has a good clinical effect in the treatment of MSA, which can improve the skin lesion symptoms and skin barrier function without increasing adverse reactions.