Esculetin (ESC) is a coumarin that is present in several plants such as Fraxinus rhynchophylla and Artemisia capillaris. Our previous study found that FR ethanol extract (FR(EtOH)) significantly ameliorated rats' liver function. This study was intended to investigate the protective mechanism of ESC in hepatic apoptosis in rats induced by carbon tetrachloride. Rat hepatic apoptosis was induced by oral administration of CCl(4). All rats were administered orally with CCl4 (20%, 0.5 mL/rat) twice a week for 8 weeks. Rats in the ESC groups were treated daily with ESC, and silymarin group were treated daily with silymarin. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) as well as the activities of the anti-oxidative enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase in the liver were measured. In addition, expression of liver apoptosis proteins and anti-apoptotic proteins were detected. ESC (100, 500 mg/kg) significantly reduced the elevated activities of serum ALT and AST caused by CCl(4) and significantly increased the activities of catalase, GPx and SOD. Furthermore, ESC (100, 500 mg/kg) significantly decreased the levels of the proapoptotic proteins (t-Bid, Bak and Bad) and significantly increased the levels of the anti-apoptotic proteins (Bcl-2 and Bcl-xL). ESC inhibited the release of cytochrome c from mitochondria. In addition, the levels of activated caspase-9 and activated caspase-3 were significantly decreased in rats treated with ESC than those in rats treated with CCl(4) alone. ESC significantly reduced CCl(4)-induced hepatic apoptosis in rats.