Non-alcoholic fatty liver disease (NAFLD) is a complex disease caused by a number of different pathogenic processes as a result of the systemic interaction between the liver and several other organs. Grape seeds proanthocyanidins extract (GSPE) potency in the liver is associated with improvement of the hepatic enzyme activities as their powerful antioxidant property results from its ability to directly scavenge free radicals and/or chelate metals. Thirty-two male albino rats were assigned into 4 equal groups of 8 rats as: Normal control group (G1): Rats fed ordinary normal diet for 12 weeks. NAFLD group (G2): Rats provided with HFD-diet for 6 weeks for NAFLD induction, followed by ordinary normal diet for another 6 weeks. NAFLD + GSPE treated group (G3): Rats fed HFD for 6 weeks (NAFLD) followed by administration of GSPE for another 6 weeks. NAFLD + GSPE + clopidogrel treated group (G4): Rats fed HFD for 6 weeks, followed by administration of GSPE and clopidogrel for additional 6 weeks. The results revealed that treatment with GSPE or in combination with clopidogrel (G3, G4) significantly decreased the higher activities of serum AST, ALT and γ GT in NAFLD induced rats (G2). Interestingly, the gene expressions ofIL-1β, PPARα, TGF-β1 and TIMP1 inliver tissue significantly down regulated in GSPE (G3) and GSPE + clopidogrel (G4) treated groups as compared with NAFLD group (G2). In conclusion, treatment with GSPE and in combination with clopidogrel is alternative therapiesand powerful anti-inflammatory, protect liver cells against fatty liver disease via restoring the hepatocytes function and inflammatory mediators.