Aim of the study: High dose acetaminophen (APAP) increases the risk of liver injury caused by oxidative stress due to accumulation of reactive species. Although N-acetyl cysteine is the standard antidote used to treat acute APAPinduced liver failure, we proposed that known antioxidant phytochemicals in Leonotis nepetifolia extracts would protect against APAP-induced hepatic injury by modulating the activities of antioxidant enzymes. Materials and methods:Methanol and aqueous extracts of L. nepetifolia were orally administered in doses ranging (250 mg/kg to 1000 mg/kg) as pre-and post-treatment with high dose APAP (550 mg/kg) to Swiss albino mice. Twenty-four hours after the final dose, animals were euthanized and blood and liver collected for liver enzymes (ALT and AST), histological assessment and antioxidant enzyme assays.Results: Methanol and aqueous extracts as pre-treatment and post-treatment protected against hepatic injury. Extracts abrogated the 14-fold and 4-fold APAP-induced increases in ALT and AST respectively, including histopathological damage (p<0.05). Extracts reversed APAP-induced 4-fold and 14-fold increases in GR and SOD activities respectively (p<0.05). Additionally, extracts reversed APAP-induced decline in GPx activity; particularly the aqueous extract as pre-treatment increased GPx activity up to 2.2-fold over saline-treated controls (p<0.05). Conclusions:Extracts, as pre-treatment and post-treatment, prevented APAP-induced hepatic injury by modulating the activities of antioxidant enzymes. Of particular interest, is the reversal of APAP-induced decrease in GPx activity and increase in SOD activity? Extract-induced increase in GPx activity would facilitate the scavenging of hydroperoxide and peroxide reactive species generated by high dose APAP. We propose that antioxidant phytochemicals in L. nepetifolia may be acting as free radical scavengers which results in reduced SOD activity.