Hepatotoxicity is considered a serious condition which can be progressed to liver damage. The hepatoprotective effect of Parkinsonia aculeata (PA) aqueous extract against acetaminophen (APAP)-induced hepatotoxicity was investigated. Wister albino ratswere orally pre-treatedwith PA aqueous extract (250mg/kgBW) for 14 days. A single toxic dose ofAPAP (800mg/kg BW) was orally administered at the 13th day. Collection of blood samples was done for the biochemical analysis, and the hepatic 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 ameliorates the 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.