The study's objective was to compare instrument performance and tissue healing when steel scalpel, ultrasonic scalpel, monopolar or bipolar electrosurgical instruments, or CO2 laser was used in an animal oral surgery model. Prospective, blinded, randomized. Adult guinea pigs (N = 70) were randomly assigned to 5 groups (14 animals per group) for excision of 2-cm, full-thickness oral mucosa using steel scalpel, ultrasonic scalpel, monopolar or bipolar electrosurgical instruments, or CO2 laser. Postoperative pain was measured indirectly using weekly body weight changes. Animals from each group were killed on days 0, 7, 14, 21, and 28. Specimens were harvested for blinded histopathological study and tensile strength measurement. Instrument performance (hemostasis, tissue coagulation, tissue sticking) and wound healing (tissue re-epithelialization, degree of inflammation) were primary outcomes. Statistical analysis was performed using analysis of variance. The ultrasonic scalpel was the best tool in controlling hemostasis, tissue coagulation, and tissue sticking. Significantly higher body weight gain ( P<.05) was noted at day 7 for monopolar and CO2 laser groups. Greatest tensile strength was seen in the steel scalpel and ultrasonic scalpel groups at the end of 28 days. Tissue re-epithelialization was fastest for the steel scalpel and ultrasonic scalpel groups (complete by day 7). Complete re-epithelialization of wounds of all treatment groups occurred by day 28. All groups had acute inflammation. Complete resolution of inflammation by day 14 took place in the steel scalpel and ultrasonic scalpel groups only. Use of the ultrasonic scalpel produced faster re-epithelialization and greater tensile strength than laser or electrosurgical instruments, with results comparable to those seen with the steel scalpel.