We aimed to compare the effectiveness of thymoquinone (TQ), most important bioactive component of black cumin, St. John wort (SJW) oil, a traditional medicinal plant used in burns, and silver sulfadiazine (AgSD), well-known anti-inflammatory agent used in modern medicine, in an experimental burn rat-model. 63 Wistar-Albino rats were randomly divided into 9 groups (n=7). TQ, SJW were administered topically and systemically but AgSD was applied topically. Epithelialization, inflammatory cell response, granulation tissue, vascularization, and fibrosis were evaluated. Malondialdehyde (MDA), total antioxidant status (TAS), total oxidant status (TOS), vitamin E, 8-hydroxy-deoxyguanosine (8-OHdG), coenzyme Q10 (CoQ10) were analyzed in serum. Topical TQ accelerated theepithelialization, enabled granulation, vascularization and fibrosis in wounds (P=0.001). Topical and systemic TQ increased Vitamin-E levels (P=0.003) but reduced TOS and 8-OHdG levels (P=0.001). Topical SJW reduced granulation and vascularization. Topical and systemic SJW decreased TOS, MDA and 8-OHdG levels (P=0.001), but increased TAS (P=0.001), and Vitamin-E levels (P=0.003). Topical AgSD reduced TOS, 8-OHdG, MDA levels (P=0.001). Topical and systemic TQ demonstrated significant advantages in accelerating wound healing process, while also enhancing antioxidant defenses and reducing oxidative damage. SJW oil, particularly in topical application, improved epithelialization and antioxidant status but showed less efficacy in systemic use. AgSD, while effective in reducing oxidative stress, was less successful in promoting wound healing and appeared to delay granulation and fibrosis. TQ offers superior protective and healing benefits, SJW is effective locally but less so systemically, and AgSD should be used cautiously, potentially combined with antioxidants to mitigate its negative impact on wound healing.