Senna occidentalis is potentially toxic to humans and animals. Its seeds are crop contaminant weeds in some localities where liver disease is prevalent. This study assessed the subacute hepatotoxicity of S. occidentalis seeds in mice model. Three groups of female Swiss Albino mice (25–28 g, aged 8–10 weeks) received distilled water (control), 400, and 1000 mg/kg extract of S. occidentalis seed, respectively. At the end of the study, body weight and liver organ weight were recorded, and tissue and blood samples were collected and analyzed. The results indicated that the extract treated groups, at both doses, showed significant (p≤0.001) decrease in mean body weight gain in the fourth week of the experiment. Besides, the extract treated groups showed significant (p≤0.001) elevation of liver enzyme markers: alanine aminotransferase and aspartate aminotransferase. Also, histopathological examinations of liver tissue showed moderate microvesicular steatosis of hepatocytes and mild inflammation in the 400 mg/kg treated group as well as marked micro- and macrovesicular steatosis, focal area necrosis, and periportal inflammation with mononuclear cell infiltration in the 1000 mg/kg treated group. Thus, these findings show that S. occidentalis seeds exhibit hepatotoxicity in mice, characterized by changes in liver tissue architecture and liver enzyme levels.