Background and Objectives Chronic wound repair is a major problem in wound treatment. Recently, several studies have suggested that carbon dioxide (CO2) laser can be used to improve the healing of chronic wounds. The aim of the present study was to preliminarily investigate the efficacy of laser debridement in treating chronic wound through a comparison of traditional instrument/surgical debridement with the ultrapulsed CO2 laser debridement in terms of wound healing, wound infection control, and wound blood perfusion. Study Design/Materials and Methods Patients with chronic wound admitted to the Wound Repair Clinic at The Affiliated Hospital of Southwest Medical University (Luzhou, China) between February 2019 and May 2019 were enrolled. They were randomly divided into two groups. The patients in one group were treated with traditional sharp instrument/surgical debridement (RT group; number of wounds: 28), while the patients in the other group were treated with ultrapulsed CO2 laser debridement (LT group; number of wounds: 26). An intergroup comparison was performed based on parameters, such as wound healing, wound infection control, and changes in wound blood perfusion. Results The wound healing rate and the total time to achieve healing were significantly better in the LT group versus the RT group at 7, 14, 21, and 28 days after treatment. The wound exudation scores were significantly higher in the LT group versus the RT group at 7, 14, and 28 days after treatment. The positive rate of pre‐debridement bacterial culture was significantly lower in the LT group versus the RD group at 14 and 28 days after treatment. The percentage of wound perfusion/normal periwound skin perfusion was significantly higher in the LT group versus the RT group at 1, 7, and 14 days after treatment. Conclusion For the treatment of chronic refractory wounds, the ultrapulsed CO2 laser exhibits higher accuracy, more effectively controls wound infection, promotes an increase in wound blood perfusion, and achieves faster wound healing compared with traditional sharp instrument/surgical debridement. Lasers Surg. Med. © 2020 Wiley Periodicals LLC