Thymoquinone (TQ) is a plant extract that has been shown to have antimicrobial, anti-inflammatory, and antioxidant effects. Because of these activities, the authors hypothesized that TQ would reduce inflammation and oxidative stress and accelerate wound closure in a rat model of deep second-degree burns. For the purposes of this study, 40 Sprague-Dawley rats were divided into five groups of eight rats each. Group 1 was the control group, group 2 was the silver sulfadiazine group, group 3 was treated with systemic TQ, group 4 received topical TQ, and group 5 was administered topical and systemic TQ. After the deep second-degree burn damage was created, daily dressing changes and TQ administration were continued in the study groups for a period of 21 days. Systemic TQ was administered intraperitoneally at a dose of 2 mg/kg/day, whereas the topical treatment was applied using a 0.5% solution. The changes in the wound site were observed macroscopically, histopathologically, microbiologically, and biochemically in all groups. The smallest necrotic areas were observed at the end of the study in the groups that were administered a combination of systemic and topical TQ, or solely topical TQ (6.1 ± 1.6 cm2 and 6.7 ± 0.4 cm2, respectively), whereas the largest necrotic areas were observed in the control group (11.2 ± 1.2cm2). The total antioxidant state levels in the control group were significantly lower than in the other groups (P < .05), whereas the total oxidative stress levels were lower in the TQ groups compared with the control group (P < .05). The lowest bacterial counts were observed in the groups treated with both topical and systemic TQ (P < .05). TQ given systemically and/or topically reduced inflammation and oxidative stress and accelerated the rate of wound closure or reepithelialization.