Background: Genfibrozil capable to attenuate the nephrotoxicity by controlling oxidative stress and proinflammatory molecules in rats. Objective: The present study investigated the possible effect of gemfibrozil (peroxisome proliferator-activated receptors-__ampersandsignalpha; agonist) in nicotine-induced acute kidney injury (AKI) in rats. Methods: Nicotine (2 mg/kg/day, intraperitoneally) was administered for 4 weeks to induce AKI in rats. Lipid profile and renal oxidative stress were measured and along with serum and renal tissue nitrite levels. Serum creatinine, blood urea nitrogen and microproteinuria were estimated along with the kidney histology, as markers of kidney function. Treatment with Gemfibrozil (30 mg/kg per oral, 4 weeks) was initiated 3 days before the administration of nicotine and continued for 4 weeks from the day of administration of nicotine. Results: Nicotine administered rats developed apparent AKI confirmed by elevated markers of kidney function and noticeable glomerulosclerosis and tubular cell degeneration. Nicotine altered lipid profile, decrease oxidative stress, assessed in terms of increase in serum thiobarbituric acid reactive substance and a marked decrease in tissue reduced glutathione. However, gemfibrozil significantly prevented the development of nicotine-AKI by reducing serum creatinine, BUN, and urinary protein, normalizing the lipid profile, reducing renal oxidative stress, and concentration of serum and renal nitrate levels. Conclusion: Gemfibrozil offers superior therapeutic options against nicotine-induced AKI, suggesting a possibility of the nephroprotective action mainly mediated through its antihyperlipidemic, antioxidant, and maybe potential to submaximal eNOS expression activation.