Objective To investigate the efficacy and safety of fractional CO2 laser in the treatment of post-acne depressed scar. Methods A total of 80 patients with post-acne depressed scar admitted to Zibo Hospital of Traditional Chinese Medicine from January to December 2023 were selected, and they were divided into the reference group and the study group by the random number method, with 40 patients in each group. The reference group was given intense pulsed light, and the study group was given fractional CO2 laser. The treatment effect, scar area, erythema area, quality of life and adverse reaction rate were compared between the two groups. Results The total effective rate of treatment in the study group (97.50%) was higher than that in the reference group (77.50%) (P <0.05). The scar area and erythema area of the study group after treatment were smaller than those of the reference group (P <0.05). The ECCA score and semi-quantitative score of acute inflammatory response in the study group after treatment were lower than those in the reference group (P <0.05). The scores of quality of life in the study group after treatment were higher than those in the reference group (P <0.05). The incidence of adverse reactions in the study group (5.00%) was lower than that in the reference group (22.50%) (P <0.05). Conclusion The application of fractional CO2 laser in the treatment of post-acne depressed scar can effectively improve the scar symptoms of patients, which is beneficial to improving the quality of life and prognosis of patients, and the incidence of adverse reactions after treatment is low, with good efficacy and safety.