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Background: In this survey, the protective effect of Prosopis farcta seed hydro-alcoholic extract against acute hepatotoxicity induced by thioacetamide in rat was studied. Methods: 30 male rats were equally divided to 3 groups. The first group received normal saline orally. The second and third group received thioacetamid (50 mg/kg intraperitoneally) three times at an interval of 24 hours. Rats in the third group received hydro-alcoholic extract of Prosopis fracta seed extract (100 mg/kg orally) for 3 weeks. Serum liver enzymes and malondialdehyde (MDA) levels were assayed. After tissue processing, histopathological changes of liver were examined under light microscopy. Data were compared using one-way ANOVA and Tukey tests at the significance level of P < 0.050. Findings: Intraperitoneal injection of thioacetamide significantly increased liver enzymes in rats (P < 0.050). Oral administration of Prosopis farcta seed extract significantly decreased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and malondialdehyde compared with the negative control rats (P < 0.050). In addition, the histopathological investigations revealed that treatment with Prosopis farcta seed extract significantly decreased hepatic necrosis and degeneration in comparison to negative control group (P < 0.050). Conclusion: These results showed the protective effect of Prosopis farcta hydro-alcoholic extract on acute liver injury in rats.