Objective To explore the clinical effect of CO2 fractional laser combined with photodynamic therapy in the treatment of severe depressed scar and analyze the factors influencing the effect of the combined therapy. Methods A total of 80 patients with severe depressed scar admitted to our hospital from January 2022 to January 2024 were selected, and they were divided into the control group and the study group by the random number table method, with 40 patients in each group. The control group was treated with CO2 fractional laser alone, and the study group was treated with CO2 fractional laser combined with photodynamic therapy. The scar status and clinical effect were compared between the two groups. Univariate and multivariate Logistic regression analyses were used to identify the independent factors influencing the effect of the combined therapy, and the receiver operating characteristic (ROC) curve was drawn to analyze the predictive efficacy. Results The scores of VSS and UNC in the two groups at 4 and 8 weeks after treatment were lower than those before treatment, and those in the study group were lower than those in the control group (P <0.05). The total effective rate of treatment in the study group was 80.00%, which was higher than 60.00% in the control group (P <0.05). There were significant differences in age, course of disease, maximum depth of scar and accompanied by skin diseases between the effective group and the ineffective group (P <0.05). Logistic regression analysis showed that disease course, complicated skin diseases, and scar depth were independent risk factors affecting the efficacy of CO2 fractional laser combined with photodynamic therapy in the treatment of severe depressed scar (P <0.05). The AUC of combined prediction of efficacy was 0.834, with a sensitivity of 90.50% and a specificity of 85.60%, which were higher than those of single-index prediction (P <0.05). Conclusion CO2 fractional laser combined with photodynamic therapy has a definite effect in the treatment of severe depressed scar, but the clinical efficacy is affected by factors such as disease course, complicated skin diseases,and scar depth. These factors should be fully considered before treatment to formulate an appropriate treatment plan.