Objective To explore the effect of negative pressure wound therapy combined with tangential excision and skin grafting on pain degree and wound healing in patients with deep burn. Methods A total of 78 patients with deep burn admitted to Liyang People’s Hospital from July 2022 to December 2023 were selected and divided into the reference group and the combination group by the random number table method, with 39 patients in each group. The reference group was treated with tangential excision and skin grafting, and the combination group was treated with negative pressure wound therapy combined with tangential excision and skin grafting. The pain degree, wound healing, quality of life, inflammatory factors levels and complications were compared between the two groups. Results The VAS score in the combination group was lower than that in the reference group (P <0.05). The wound healing time and granulation time in the combination group were shorter than those in the reference group, and the frequency of dressing change was less than that in the reference group (P <0.05). After treatment, the quality of life scores in the combination group were higher than those in the reference group (P <0.05). After treatment, the levels of IL-6, CRP and TNF-α in the combination group were lower than those in the reference group (P <0.05). The incidence of complications in the combination group was 5.13%, which was lower than 23.08% in the reference group (P <0.05). Conclusion The application of negative pressure wound therapy combined with tangential excision and skin grafting in patients with deep burn is effective, which can effectively relieve the pain degree, promote wound healing. It is beneficial to promote the resolution of the inflammatory response, improve patients’ quality of life. Additionally, the incidence of adverse reactions after treatment is low and the safety is high.