The initiation and progression of nonalcoholic fatty liver disease (NAFLD) include imbalanced lipid metabolism, insulin resistance (IR) and oxidative stress. Consequently, grape seed proanthocyanidin extract (GSPE) showed very beneficial effect against the NAFLD metabolic disruptions, via its antioxidant, anti-inflammatory and lipolytic properties. Clopidogrel also can reduce the oxidative stress and inflammation. Thirty-two male albino rats were divided into four equal groups of 8 rats; Group I: Normal control group (G1): Rats fed ordinary normal diet for 12 weeks. Group II: NAFLD group (G2): Rats fed HFD-diet for 6 weeks for NAFLD induction, followed by ordinary normal diet for another 6 weeks. Group III: NAFLD+GSPE treated group (G3): Rats fed HFD for 6 weeks (NAFLD) followed by administration of GSPE for another 6 weeks. Group IV: NAFLD + GSPE + Clopidogrel treated group (G4): Rats fed HFD for 6 weeks (NAFLD), followed by administration of GSPE and clopidogrel for additional 6 weeks. The results showed that treatment with GSPE (G3) or in combination with Clopidogrel (G4) significantly decreased the higher serum total cholesterol, triacylglycerols and ferritin concentrations that were observed in NAFLD-induced group (G2).Interestingly, the hepatic inflammatory mediators VEGF, PDGF α and MAPK gene expression levels were significantly down-regulated in GSPE (G3) or GSPE and Clopidogrel co-treated (G4) groups as compared with NAFLD-induced group (G2). In conclusion, treatment with GSPE alone or with Clopidogrelis a potent hypolipidemic and anti-inflammatory, restoring hepatic cell function and alleviates the oxidative stress and inflammation related to NAFLD in rats.