Objective: To analyze the effect of vacuum sealing drainage (VSD) plus skin grafting on deep burns and the risk factors of postoperative infection. Methods: A retrospective analysis was conducted on 124 patients with deep burns who were admitted to the Taizhou People's Hospital from February 2019 to February 2021. The 55 patients who underwent traditional dressing change therapy plus second-stage skin grafting became the control group. The remaining 69 patients treated with first stage VSD plus second-stage skin grafting became the observation group. Wound healing time, hospital stay, postoperative infection, wound closure success rate, pain degree, and scar hyperplasia were recorded and compared between the two groups. Logistic regression was used to analyze the risk factors of postoperative infection in patients. Results: Compared with the control group, the observation group had a shorter time of wound healing and hospital stay, lower postoperative wound infection rate and lung infection rate, higher success rate of wound closure, lower pain degree scores on the 7th day after the operation, and less scar hyperplasia (all P < 0.05). Logistic regression analysis revealed that burn degree, treatment plan, proportion of burn area, and wound healing time were the factors affecting postoperative infection in patients. Conclusion: VSD plus skin grafting have significant effects on deep burns. This combined treatment reduced the occurrence of the wound infection, relieved pain, shortened the healing time and hospitalization time, and reduced the proliferation of scars in the later stage.