People especially youth are used to consume overdoses from pain relief drugs to kill pain. Acetaminophen (AC) that has the commercial name Panadol is the more famous drug. AC overdose (750 mg/kg) can cause hepatotoxicity with oxidative stress as one of the possible mechanisms mediating the event. The present study aimed to explore the therapeutic effects of 200 mg/kg of fenugreek (FEN) on AC-induced hepatotoxicity, for seven consecutive days. Treatment with FEN prevented the AC-induced hepatotoxicity, by increased protein, albumin, and decrease liver function levels. These biochemical analyses authenticated with the histological improvement in the hepatic tissue. The improvement of hepatic histological picture come in accordance with the reducing expression of caspase-3 and vascular endothelial growth factor (VEGF) in hepatic cytoplasm when compared with AC-treated animals. In conclusion, FEN has a protective role against AC-induced hepatotoxicity by enabling hepatocyte regeneration and reducing inflammatory activity.