Objective To investigate the efffcacy and safety of liquid nitrogen cryotherapy combined with 5-aminolevulinic acid photodynamic therapy in the treatment of actinic keratosis. Methods A total of 80 patients with actinic keratosis admitted to our hospital from January 2022 to January 2024 were selected, and they were divided into the control group (n=40) and the observation group (n=40) according to different treatment regimens. The control group received liquid nitrogen cryotherapy, and the observation group received liquid nitrogen cryotherapy combined with 5-aminolevulinic acid photodynamic therapy. The clinical efficacy, regression rate of lesion area, lesion severity, pain intensity, adverse reactions and recurrence rate were compared between the two groups. Results The total effective rate of the observation group was 92.50%, which was higher than 62.50% of the control group (P<0.05). At 4, 12 and 24 weeks after treatment, the regression rates of lesion area in the observation group were higher than those in the control group, and the lesion severity scores were lower than those in the control group (P<0.05). There were no statistically signiffcant differences in VAS scores between the two groups immediately after treatment, 24 h and 72 h after treatment (P>0.05). The incidence of adverse reactions in the observation group was lower than that in the control group (P<0.05). The recurrence rates at 12 weeks, 24 weeks and total recurrence rate in the observation group after treatment were lower than those in the control group (P<0.05). Conclusion Liquid nitrogen cryotherapy combined with 5-Aminolevulinic acid photodynamic therapy achieves better clinical efffcacy in the treatment of actinic keratosis. It can effectively promote lesion regression, reduce the incidence of adverse reactions and recurrence rate, without increasing treatment-related pain. It has favorable safety.