Background: Renal ischemia–reperfusion injury (IRI) is a major clinical problem associated with kidney transplantation, leading to high mortality and morbidity. IRI involves activation of oxidative stress and inflammatory pathways, eventually leading to cell death and organ failure. Piperine is a phenolic active ingredient of black pepper, which showed promising antioxidant and anti-inflammatory potential. Objectives: We hypothesized that piperine would protect against renal IRI in rats via inhibition of oxidative stress and inflammation. Materials and Methods: Male Sprague Dawley rats were subdivided into four groups; sham, IR, IR + piperine, and sham + piperine. All animals have been treated for 4 days with either vehicle or piperine (100 mg/kg/day). One hour after the last piperine or vehicle administration, animals were subjected to bilateral renal ischemia for 45 min by clamping both renal pedicles, followed by reperfusion for 24 h. At the end of the experiments, kidneys were harvested for the determination of lipid peroxidation (malondialdehyde [MDA]), reduced glutathione (GSH), inflammatory and apoptotic markers, and histopathology. Serum levels of creatinine and urea have been determined. Results: Induction of renal IR increased renal oxidative stress (increased MDA and decreased GSH) and the expression levels of inflammatory and proapoptotic genes (nuclear factor-kappa B, inducible nitric oxide synthase, cyclooxygenase-2, and caspase-3). Moreover, serum levels of creatinine and urea were significantly elevated. Alternatively, pretreatment of the animals with piperine resulted in normalization of these parameters. Conclusion: The results showed that piperine pretreatment protects against IRI in rat kidneys via mechanisms involving amelioration of oxidative stress along with inflammatory and apoptotic pathways.