Cocaine (COC) produces hepatotoxicity by a mechanism, which remains undefined, but has been linked to its oxidative metabolism. Ketamine (KET) is also a potentially hepatotoxic agent. The abuse of KET with COC is currently popular among young abusers therefore; this study was conducted to investigate the possible potentiation of COC-mediated hepatotoxicity (CMH) by KET. Male Sprague Dawley (SD) rats were administered oral KET hydrochloride for three consecutive days at a dose of 100 mg/kg with and without a single dose of COC (5 mg/kg, i.v.) administered 18 h after the last KET dose. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Liver reduced glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that KET pretreatment potentiated the hepatotoxicity of COC. Serum ALT and AST were significantly elevated with the combined KET and COC treatment versus all other treatments. While COC alone resulted in focal inflammatory cell infiltration, COC administration after KET pretreatment produced sub-massive hepatic necrosis. Hepatic GSH content was significantly reduced in KET-pretreated COC group compared to the other treatment groups, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the KET-pretreated COC group. In addition, norcocaine (NC) was only detected in the plasma of rats received COC after KET pretreatment. In conclusion, this study demonstrates that KET pretreatment potentiates the hepatotoxicity of COC as revealed by an array of biochemical and morphological markers most probably due to increase in COC oxidative metabolism.