Objective To investigate the effect of VSD vacuum aspiration combined with free skin graft repair on the incidence of infection in patients with Ⅲ and Ⅳ degree burns. Methods A total of 60 patients with Ⅲ and Ⅳ degree burns admitted to our hospital from August 2022 to August 2024 were selected as the research objects. They were divided into control group and observation group by random number table method, with 30 patients in each group. The control group was treated with free skin graft repair, and the observation group was treated with VSD vacuum aspiration on the basis of the control group. The clinical efficacy, inflammatory factor level, infection and scar hyperplasia severity were compared between the two groups. Results The total effective rate of treatment in the observation group was 96.67%, which was higher than 80.00% in the control group, and the difference was statistically significant (P <0.05). The levels of IL-6, IL-8 and CRP in the observation group were lower than those in the control group at 7 days after operation, and the differences were statistically significant (P <0.05). The incidence of infection in the observation group was 3.33%, which was lower than 16.67% in the control group, and the difference was statistically significant (P <0.05). The severity of scar hyperplasia in the observation group was better than that in the control group, the difference was statistically significant (P <0.05). Conclusion For patients with Ⅲ and Ⅳ degree burns, VSD vacuum aspiration combined with free skin graft repair can reduce the risk of infection, effectively reduce the severity of scar formation, reduce the level of inflammatory factors, and improve the therapeutic effect, which has good clinical application value.