The current study investigated the effects of Olea europaea L. cv. Nepal (OEN) leaf extract on obesity-related disorders in rabbits. OEN extract, in dose 100 mg/kg body weight, significantly reduced cholesterol (TC), triglycerides (TAG), and inflammatory markers (MCP-1, VCAM-1, IL-6, IL-1β, TNFα, NF-κB) in both preventative and treatment groups. In addition, heart tissue displayed near-normal collagen fiber distribution. LC-HRESIMS analysis tentatively identified 20 metabolites (1–20) in OEN, including lignans, secoiridoids, and triterpenoids. Network pharmacology analysis suggested 8-hydroxy-p-menth-1-en-7-oic-acid (13), 6,7-dihydroxy-2H-1-benzopyran-2-one 6-O-d-glucopyranoside (5), and 3-hydroxy-12-oleanen-28-oic-acid (20) as key antihyperlipidemic compounds, potentially targeting pathways involved in hyperlipidemia regulation. Furthermore, in silico studies revealed that lignans (compounds 1, 2, and 16) from OEN may bind and inhibit HMG-CoA reductase, a crucial enzyme in cholesterol metabolism. These results indicate the potential of using OEN leaf extract as a therapeutic strategy for managing hyperlipidemia and inflammation associated with obesity. More investigation is necessary to confirm and validate these results and explore the extract’s full therapeutic potential.