Background: Obesity is one of the most prevailing health issues globally. Aims: The current study was conducted to evaluate the biochemical effects of Vitis vinifera leaves petroleum ether extract (VLPE) against high-fat diet induced obesity in rats. Methods: VLPE was administrated in a dose 200 mg/kg body weight. Liver enzymes, lipid profile, oxidative stress, apoptotic and inflammatory biomarkers as apelin, paraxonase -1 (PON-1), Nuclear Factor Kappa beta (NFkB), Monocyte chemoattractant protein-1 (MCP 1) and (B-cell lymphoma 2) BCl2 were assayed. Also, glucose, leptin and lipase levels were evaluated. Moreover, the phytochemicals profile of VLPE was characterized through chromatographic and spectroscopic tools after saponification. Results: Post-treatment of obese rats with VLPE, a significant decrease in the bodyweight gain was detected compared control group. In addition, reduction in MDA while an elevation in GSH, apelin and PON1 levels post treatment of obese -rats with VLPE was observed. Also, a noticeable improvement in other parameters was recorded upon treating HFD-rats with VLPE. Post treatment of obese rats with Vitis vinifera; normal histological structure of hepatic lobule with mild inflammatory cells infiltration in the portal area was examined. Kidney of obese rats showed vacuolar degeneration in the epithelial cells lining the tubules, while obese rats treated with Vitis vinifera extract and Orlistat drug showed no vascular congestion and no inflammation. Concerning the characterization of VLPE, twenty- three compounds, as well as fifteen fatty acids, were identified in unsaponifiable and saponifiable fractions, respectively. Unsaponifiable fraction constituted of hydrocarbons (13.86% of total unsaponifiable matter), fatty alcohol (7.20%) and sterol (2.65 %) and triterpene compounds (2.09%). Column chromatography of the USM afforded lupeol, cholesterol, campesterol and -sitosterol in addition one fatty alcohol 1-triacontanol. Conclusion: According to the finding results, a lipoidal matter of Vitis vinifera leaves possesses multi-functional anti-obesity activities that can be used as a phytochemical functional food