Objective To explore the efficacy and safety of photodynamic therapy combined with drugs in the treatment of actinic keratosis. Methods A total of 60 patients with actinic keratosis admitted to Jining Dermatosis Prevention and Treatment Hospital from January 2022 to December 2023 were selected as the research subjects, and they were divided into the control group and the observation group by the random number table method, with 30 patients in each group. The control group was treated with imiquimod, and the observation group was treated with photodynamic therapy combined with drugs. The skin lesions, treatment effect, adverse reactions and recurrence rate were compared between the two groups. Results After treatment, the skin lesion area and number 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). The total effective rate of treatment in the observation group was 96.67%, which was higher than 73.33% in the control group (P <0.05). The incidence of adverse reactions in the observation group was 3.33%, which was lower than 20.00% in the control group (P <0.05). The recurrence rate in the observation group was 3.33%, which was lower than 23.33% in the control group (P <0.05). Conclusion The application of photodynamic therapy combined with drugs in the treatment of patients with actinic keratosis can effectively reduce the skin lesion area, improve the treatment effect, and reduce the incidence of adverse reactions and the recurrence rate of the disease, which is worthy of clinical application.