Objective To explore the clinical effect of ALA photodynamic therapy combined with isotretinoin soft capsule in the treatment of nodular cystic acne. Methods A total of 40 patients with nodular cystic acne admitted to the Department of Dermatology, Zhongshan District People's Hospital of Liupanshui from January 2022 to January 2023 were selected as the research objects. They were divided into reference group and experimental group by random number table method, with 20 patients in each group. The reference group was treated with antibiotics combined with isotretinoin soft capsules, and the experimental group was treated with ALA photodynamic therapy combined with isotretinoin soft capsules. The clinical efficacy, incidence of adverse reactions and recurrence rate of the two groups were compared. Results The total effective rate of treatment in the experimental group was 95.00%, which was higher than 60.00% in the reference group (P <0.05). The incidence of adverse reactions in the experimental group was 10.00%, which was lower than 35.00% in the reference group (P <0.05). The recurrence rate of disease in the experimental group was 5.00%, which was lower than 30.00% in the reference group (P <0.05). Conclusion ALA photodynamic combined with isotretinoin soft capsule is effective in the treatment of nodular cystic acne, which can improve the clinical efficacy, reduce the incidence of adverse reactions and reduce the recurrence of the disease. It is worthy of clinical reference.