Hypercholesterolemia is a major risk factor for cardiovascular diseases. This study investigated the cholesterol-lowering potential of β-caryophyllene in a rat model. Hypercholesterolemia was induced by feeding male Wistar rats a high cholesterol and fat diet for 2 weeks. This was followed by oral administration of β-caryophyllene to hypercholesterolemic rats at 30, 100 and 300 mg/kg b.w. for 4 weeks. A dose of 30 mg/kg of β-caryophyllene significantly lowered serum total cholesterol, low density lipoprotein and the atherogenic index and significantly increased high density lipoprotein level. Moreover, it ameliorated liver injury as evidenced by decreasing hepatomegaly, macrovesicular steatosis and the activity of hepatic marker enzymes alanine aminotransferase and aspartate aminotransferase. Furthermore, it increased the activity of the antioxidant enzyme superoxide dismutase. This dose of β-caryophyllene significantly inhibited the activity of hepatic hydroxy-methylglutaryl coenzyme A reductase. Higher doses (100 and 300 mg/kg) of β-caryophyllene, however, did not induce significant beneficial effects on the studied parameters. These observations demonstrate that β-caryophyllene has a cholesterol-lowering effect on hypercholesterolemic rats, thus offering protection against hypercholesterolemia-induced diseases such as atherosclerosis and fatty liver.