Hepatotoxicity is considered a serious condition which can be progressed to liver damage. The hepatoprotective effect oParkinsonia aculeata (PA) aqueous extract against acetaminophen (APAP)-induced hepatotoxicity was investigated. Wistealbino rats were orally pre-treated with PA aqueous extract (250 mg/kg BW) for 14 days. A single toxic dose of APAP (800 mg/k BW) was orally administered at the 13th day. Collection of blood samples was done for the biochemical analysis, and the hepati tissue was collected for histopathological examinations. Our results indicate that PA aqueous extract exhibit a significant hepatoprotective effect by ameliorating APAP-induced alterations of serum aspartate transaminase (AST), alanine transaminase (ALT), total protein (TP), albumin (ALB), and bilirubin (total and indirect). Moreover, the prior administration of PA amelioratethe hepatotoxic changes induced by APAP as confirmed by liver histopathology. Taken together, the previous results demonstrated that the PA pretreatment provide significant hepatoprotective effect against the APAP-induced hepatotoxicity in animal models, thus PA could be a potential herbal medication that can be used in the future prevention of liver intoxication.