This work intended to determine the therapeutic efficacy of Rhubarb (Rhu) (Rheum rhabarbarum, family Polygonaceae) rhizome extract on lipid profile and hepatic functions and explore its mechanism as an antioxidant agent in hypercholesterolemic rats. Hypercholesterolemia was induced by feeding the rats with a high-cholesterol diet (HCD) for 4 weeks. Fifty rats were distributed into 5 groups: 1-control, 2-HCD, 3-HCD+ Atorvastatin (Atorva) (20 mg/kg), 4-HCD+Rhu extract (75 mg/kg), and 5-HCD+Rhu extract (150 mg/kg). Serum lipid profiles [TC, HDLc, LDLc, VLDLc, and TG], hepatic function enzymes [ALT, AST, and ALP], and antioxidants markers [MDA, SOD, and CAT] were assessed. Besides, the hepatic histopathological changes were examined in all groups. The results revealed that alkaloids, flavonoids, saponins, terpenes, and anthraquinones were high in Rhu extract. The HCD group showed significantly elevated lipid levels, hepatic dysfunction, and oxidative stress relative to the control group (p ≤ 0.05). Hepatic tissues had severe changes, increased lipid droplets within many hepatocytes, congestion, and inflammation of hepatic sinusoids. Treatment with Rhu extract at 150 mg/kg significantly corrected and restored these changes. Rhu extract significantly reduced serum lipid profile and alleviated hepatic function. In addition, it significantly restored the antioxidant enzymes activities and reduced lipid peroxidation relative to the HCD group (p ≤ 0.05). These findings suggest that Rhu extract has markedly hypolipidemic and hepatoprotective effects. Its antioxidant active compounds could explain the underlying mechanics. Therefore, Rhu extract might be developed as a therapeutic agent for managing hypercholesterolemia. Further in-depth investigations of its mechanism are needed.