Objective To explore the efficacy and safety of 308 nm excimer laser combined with mometasone furoate cream in the treatment of patients with palmoplantar pustulosis. Methods A total of 88 patients with palmoplantar pustulosis admitted to Sengong Hospital of Shaanxi Procince from January 2021 to October 2023 were selected as the research subjects. According to different treatment plans, they were divided into the control group and the study group, with 44 patients in each group. The control group was treated with 308 nm excimer laser, and the study group was treated with 308 nm excimer laser combined with mometasone furoate cream. The treatment effect, symptom severity, disappearance time of symptoms and signs, quality of life, adverse reactions and recurrence were compared between the two groups. Results The total effective rate of treatment in the study group (95.45%) was higher than that in the control group (79.55%) (P <0.05). After treatment, the scores of scale, blister, erythema, pustule and subjective symptoms in the study group were lower than those in the control group (P <0.05). The disappearance time of itching, scale, erythema and pain symptoms and signs in the study group was shorter than that in the control group (P <0.05). After treatment, the scores of each dimension of DLQI in the study group were lower than those in the control group (P <0.05). The incidence of adverse reactions in the study group was 2.27%, which was lower than 13.64% in the control group (P <0.05). The recurrence rate in the study group was 2.27%, which was lower than 18.18% in the control group (P <0.05). Conclusion The application of 308 nm excimer laser combined with mometasone furoate cream in the treatment of patients with palmoplantar pustulosis can effectively relieve their clinical symptoms, shorten the disappearance time of symptoms and signs, has the effect of enhancing efficacy and reducing toxicity, and is beneficial to improving the quality of life of patients. At the same time, it can reduce the incidence of adverse reactions and the recurrence rate, with high application efficacy and safety.