Renal ischemia/reperfusion (I/R) is a common cause of acute kidney injury and remote liver damage is an ultimate negative outcome. Current treatments for renal I/R typically involve the use of antioxidants and antiinflammatory to protect against oxidative stress and inflammation. Xanthine oxidase (XO) and PPAR-γ contribute to renal I/R-induced oxidative stress; however, the crosstalk between the two pathways remains unexplored. In the present study, we report that XO inhibitor, allopurinol (ALP), protects kidney and liver after renal I/R by PPAR-γ activation. Rats with renal I/R showed reduced kidney and liver functions, increased XO, and decreased PPAR-γ. ALP increased PPAR-γ expression and improved liver and kidney functions. ALP also reduced inflammation and nitrosative stress indicated by reduction in TNF-α, iNOS, nitric oxide (NO), and peroxynitrite formation. Interestingly, rats co-treated with PPAR-γ inhibitor, BADGE, and ALP showed diminished beneficial effect on renal and kidney functions, inflammation, and nitrosative stress. This data suggests that downregulation of PPAR-γ contributes to nitrosative stress and inflammation in renal I/R and the use of ALP reverses this effect by increasing PPAR-γ expression. In conclusion, this study highlights the potential therapeutic value of ALP and suggests targeting XO-PPAR-γ pathway as a promising strategy for preventing renal I/R injury