This study was conducted to investigate the protective effect of Asteracantha longifolia Linn (Acanthaceae) plant extract on carbon tetrachloride (CCl4)- and paracetamol-induced acute hepatotoxicity in mice. Hepatotoxicity was induced by the administration of a single intraperitoneal dose of CCl4 (0.5 mL kg(-1) CCl4 in olive oil) in one model and in the other by administration of paracetamol (300 mg kg(-1) in saline) orally, after a 16-h fast. An aqueous extract of the whole plant (0.9 g kg(-1)) was used on a pre- and post-treatment basis. Asteracantha reduced the alanine aminotransferase (ALT) level by 69.32% (P < 0.001) and increased the liver reduced glutathione level by 64.65% (P < 0.001) in the pre-treated group, 4 days after the administration of CCl4. A similar pattern was observed in the pre-treated group 4 h after the administration of paracetamol with a reduction in serum levels of ALT, aspartate aminotransferase and alkaline phosphatase enzymes by 65.04, 55.79 and 45.75% respectively (P < 0.001). Plant extract also increased the glutathione concentration of the liver significantly (P < 0.001). Histopathological studies also provided supportive evidence for results from the biochemical analysis with marked improvement in liver architecture being observed in the Asteracantha-treated groups. Pre-treatment showed better results than post-treatment in both hepatotoxic models. Overall results indicate that the aqueous extract of Asteracantha longifolia possesses hepatoprotective effects on CCl4- and paracetamol-induced hepatotoxicity in mice.