Cardiovascular disease (CVD) are a major public health problem, as they are among the leading causes of mortality worldwide. Tripodanthus acutifolius (TA) is a hemiparasite plant used for medicinal purposes with great antioxidant capacity. However, little is known about its hypolipemic effect. Thus, the aim of this study was to evaluate the effects of the hydroalcoholic extract of Tripodanthus acutifolius leaves in hypercholesterolemic Wistar rats. The animals were divided into: (1) NC (Normocaloric Control); (2) HC (Hypercaloric Control); (3) Oral Simvastatin Suspension 10mg/kg (SIM); (4) TA extract 50mg/kg (TA 50mg/kg) and (5) TA 100mg/kg. The in vitro antioxidant activity assay demonstrated that TA shows high antioxidant capacity. The in vivo findings demonstrated that TA supplementation resulted in significant decreases (p<0.05) in Total Cholesterol (TC), Triglycerides (TG) and Low density lipoprotein (LDL) levels, whereas High density lipoprotein (HDL) levels increased significantly in all TA-supplemented groups in relation to the HC group. Hepatic, renal and cardiac function markers improved during supplementation. Serum adiponectin levels increased significantly, whereas C-reactive protein (PCRus) levels decreased in the TA-supplemented in relation to the HC group. Catalase (CAT), superoxide dismutase (SOD) and gluthatione peroxidase (GPx) activities, as well as polyphenols, vitamin C (VitC) and total gluthatione (GSH), increased significantly in the TA-supplemented groups treated when compared to the HC group. Concerning oxidative damage to biomolecules, TA showed a protective effect on lipids, proteins and DNA. Regarding the histological analysis of the aortic artery, TA treatment was able to decrease aortic vasculature. Therefore, TA is rich in antioxidant compounds and may be an alternative for the treatment of hypercholesterolemia.