Abstract Fipronil (FPN), a phenylpyrazole insecticide, has been receiving increased attention owing to its toxicity, which is largely mediated through its effects on antioxidant systems. The present study was undertaken to assess the effects of resveratrol (RSV) and curcumin (CUR) on oxidative damage induced by FPN. Forty mature male Wistar rats were randomized into five groups (n = 8 per group): the first group was the control; the second was administered FPN (10 mg/kg); and the third, fourth, and fifth were co-treated with RSV (10 mg/kg), CUR (200 mg/kg), and their combination, respectively, 2 h prior to FPN administration. All animals were dosed via oral gavage for 4 weeks. FPN significantly (p < 0.05) elevated the sera of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (GGT), urea, creatinine, and cholesterol levels, whereas serum total protein, albumin, and triglyceride levels were significantly (p < 0.05) decreased, compared to those of the control group. Reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were decreased (p < 0.05) in the FPN-treated group compared to those in the control group; however, malondialdehyde (MDA) and nitric oxide (NO) levels were markedly increased (p < 0.05) in the hepatic, renal, and brain tissues. Co-treatment with RSV or CUR alleviated (p ˂ 0.05) the increased lipid peroxidation and changes in enzymatic/nonenzymatic antioxidants induced by FPN; all these variables mostly returned to normal levels with the combined of RSVand CUR treatment. In conclusion, RSVand/or CUR relieved and synergistically reversed the FPN-induced tissue oxidative injury, probably by improving the antioxidant defenses via their free radical scavenging and antioxidant characteristics.