Objective To analyze the clinical effect of ultra-pulsed CO2 fractional laser combined with microneedling therapy in patients with depressed acne scars. Methods A total of 100 patients with depressed acne scars admitted to Changchun Zhongyan Plastic Surgery Hospital from January 2024 to December 2025 were selected, and they were divided into the control group and the study group by the random number table method, with 50 patients in each group. The control group was given ultra-pulsed CO2 fractional laser, and the study group was given ultra-pulsed CO2 fractional laser combined with microneedling therapy. The acne scar severity, treatment effect, skin barrier function, adverse reaction rate, recurrence rate and satisfaction rate were compared between the two groups. Results After treatment, the ECCA score of the study group was lower than that of the control group (P <0.05). The total effective rate of the study group (96.00%) was higher than that of the control group (84.00%) (P <0.05). After treatment, the transepidermal water loss in the study group was lower than that in the control group, and the stratum corneum hydration was higher than that in 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 recurrence rate of the study group was lower than that of the control group, and the satisfaction rate was higher than that of the control group (P <0.05). Conclusion Ultra-pulsed CO2 fractional laser combined with microneedling therapy is effective in the treatment of depressed acne scars. It can reduce the severity of acne scars and improve skin barrier function, without increasing the incidence of adverse reactions after treatment, and help to lower the recurrence rate and improve patient satisfaction.