Objective To investigate the efficacy and safety of supramolecular salicylic acid combined with nano microneedle in the treatment of closed comedo. Methods A total of 120 patients with closed comedo admitted to Jiangmen Dermatology Hospital from January 2022 to December 2024 were selected as the research subjects. According to the random number table method, they were divided into the control group and the experimental group, with 60 patients in each group. The control group received supramolecular salicylic acid treatment, and the experimental group received supramolecular salicylic acid combined with nano microneedle treatment. The treatment effect, adverse reactions and cosmetic effect satisfaction were compared between the two groups. Results The total effective rate of treatment in the experimental group was 96.67%, which was higher than 80.00% in the control group (P <0.05). The incidence of adverse reactions in the experimental group was 10.00%, which was lower than 30.00% in the control group (P <0.05). The cosmetic effect satisfaction rate in the experimental group was 90.00%, which was higher than 66.67% in the control group (P <0.05). Conclusion Supramolecular salicylic acid combined with nano microneedle has a good effect in the treatment of closed comedo, with fewer adverse reactions. It can improve patients' satisfaction with cosmetic effect, with definite efficacy and safety.