Abstract: Background and Objective: Ischemia-reperfusion-induced acute renal injury is a common clinical problem. The current article investigates the effects of oleuropein and thymoquinone combination in the prophylaxis of renal ischemia-reperfusion-induced injury in rats. Materials and Methods: Thirty rats were divided into five groups, G1: Sham operation group, G2: IR group, G3: IR+Thymoquinone (10 mg kg–1, p.o.) G4: IR+Oleuropein (50 mg kg–1, p.o.) and G5: IR-TQ (10 mg kg–1, p.o.)+OP (50 mg kg–1, p.o.). A pre-treatment was given for three weeks before IR surgery. The blood urea nitrogen (BUN), uric acid and serum creatinine were analyzed in serum. The homogenate of kidney tissues was prepared for the estimation of the anti-oxidant parameters like Glutathione Peroxidase (Gpx), Superoxide Dismutase (SOD), Catalase (CAT) and Malondialdehyde (MDA). Results: The rats in G2 (IR) showed high levels of creatinine (4.11±0.18 mg dL–1), BUN (131.76±10.56 mg dL–1) and uric acid (1.72±0.14 mg dL–1) as compared to G1 (sham-operated rats). Further, the increased levels of MDA (10.54±0.77 nmol mg–1 protein) and low levels of SOD (78.92±3.46 U mg–1 protein), CAT (23.49±1.93 U mg–1 protein) and GSH-Px (26.53±0.64 U mg–1 Protein) activity was evidenced in the IR group. The combination treatment group G5 (IR-TQ-OP) showed the best nephroprotective activity among all the treatment groups, as the kidneys were least affected by the IR-induced renal inflammation and oxidative injuries. It was followed by IR-TQ and then IR-OP. All these observations were corroborated by the findings of histopathological investigations. Conclusion: Simultaneous administration of TQ and OP significantly altered the experimentally induced renal function due to ischemia/reperfusion.