Objective To explore the advantages of CO2 fractional laser combined with salicylic acid in the treatment of depressed facial acne scar. Methods A total of 62 patients with depressed facial acne scar treated in our hospital from July 2021 to December 2022 were selected as the research objects. According to the random number table method, they were divided into control group and observation group, with 31 patients in each group. The control group was treated with a single regimen (CO2 fractional laser), and the observation group was treated with a combined regimen (CO2 fractional laser combined with salicylic acid). The clinical efficacy, scab shedding time, skin lesion score, adverse reactions and quality of life score were compared between the two groups. Results The total effective rate of the observation group after treatment was 96.77%, which was higher than 74.19% of the control group (P <0.05). The time of crust shedding in the observation group was shorter than that in the control group (P <0.05). The skin lesion score of the observation group was lower than that of the control group (P <0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P >0.05). The quality of life score of the observation group was higher than that of the control group (P <0.05). Conclusion The application of CO2 fractional laser combined with salicylic acid in patients with depressed facial acne scar can improve the clinical efficacy, accelerate the shedding of crusts, reduce the symptoms of skin lesions, improve the quality of life, and have good safety.