The initiation and progression of nonalcoholic fatty liver disease (NAFLD) include imbalanced lipid metabolism, insulin resistance (IR) and oxidative stress. Consequantly, grape seeds proanthocyanidins extract (GSPE) have lipolytic properties and showed very positive effects against the NAFLD metabolic disruptions. The present study aim to investigate the antioxidant and anti-inflammation effects of treatment of GSPE alone or in combination with antiplatelet drug (Clopidogrel) against high fat diet (HFD)-induced NAFL, in which 32 male albino rats were assigned into four equal groups of 8 rats: 1. Normal control group (G1) of normal standard-feeding rats for 12 weeks, 2. NAFL group (G2) of HFD-induced NAFL rats during 6 weeks, followed by normal feeding for another 6 weeks, 3. GSPE treated group (G3) of the NAFL rats followed by GSPE treatment for another 6 weeks, and 4. GSPE and clopidogrel co-treated group (G4) of the NAFL rats followed by GSPE and clopidogrel co-treatment for other 6 weeks. The results showed that treatment with GSPE alone or with clopidogrel significantly decreased the serum levels of total cholesterol, triglycerides (TG) and ferritin (G3,G4) that were significantly increased due to NAFL induction (G2), and significantly downregulated the liver tissue inflammatory mediators VEGF, PDGFα, and MAPK gene expressions (G3,4)that were significantly upregulated by NAFL induction (G2). In conclusion, treatment with GSPE alone or with antiplatelet alleviates the hepatic oxidative stress and inflammation associated with HFD-induction of NAFL in rats.