Background: Apocynin (4-hydroxy-3-methoxyacetophenone) which isolated from the traditional medicinal plant Picrorhiza kurroa, is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of NADPH oxidase and of the concomitant ROS production. Apocynin also proved to be a potent anti-inflammatory agent, based on the selective inhibition of the production of ROS by activated human PMNs. Aim of the Study: to explore the protective effect of Apocynin and the NADPH oxidase inhibitor on kidney damage induced by ischemia/reperfusion (I/R) in a rat model. Subjects and Methods: Fourty male albino rats were categorized into four equal groups of 10. Group 1: Sham operated control group, Group 2: Ischemia / reperfusion (I/R) group; which underwent bilateral renal ischemia for 1 hour followed by a 23 hour reperfusion, Group 3: 4-week Apocynin treated group in which rats received Apocynin with a  dose  o16 mg/kg /day for 4 weeks followed by bilateral renal ischemia for 1 hour then 23 hour reperfusion afterwards , and Group 4: 8-week Apocynin treated group in which rats received Apocynin with a  dose of 16 mg/kg /day for 8 weeks then bilateral renal ischemia for 1 hour followed by 23 hour reperfusion. After reperfusion, the animals were sacrificed, the blood samples were collected for determination of blood urea nitrogen, serum creatinine, 24 hour urine were collected for determination of creatinine clearance. Kidneys of all animals were harvested and evaluated biochemically through determination of tissue MDA, MPO, GPX and catalase level. Results: Kidney tissue MDA, MPO, serum BUN and Creatinine levels were found to be significantly higher in the I/R group. GPx level showed a significant decrease, while there was a slight decrease in Catalase level when compared with Sham operated group. Creatinine clearance was impaired in renal I/R group. Renal I/R injury has also induced an extensive tubular necrosis, glomerular damage, and apoptosis. Apocynin significantly reduced MDA and MPO and increased GPX and catalase in both treatment groups when compared to the I/R group (p< 0.001). The elevated BUN and creatinine levels were significantly reduced in treatment groups, also creatinine clearance was restored to around normal value. Conclusion: with accordance to the findings and outcome of the present study, Apocynin has exerted protective effects against ischemia/reperfusion injury by ameliorating the kidney damage induced by I/R injury to a significant extent. However, there was no significant difference in the outcome if the treatment was extended from 4 to 8 weeks.