Abstract: Sclerocarya birrea (Hochst) is widely used in Nigeria and some African countries as medicine for the treatment of various ailments. In the present study the effect of the aqueous extract of Sclerocarya birrea was investigated against alcohol-carbon tetrachloride induced hepatocellular injury in rats over a period of 21 days. The aqueous stem bark extract was administered orally by gavage to the rats at a dose of 2, 5 and 8 mg kg-1 body weight, respectively from days 15 to 21, while a single dose of carbon tetrachloride (CCl4; 0.1 mL kg-1 body weight in pure corn oil) was administered subcutaneously on day 20 to induce hepatotoxicity. At the of end the experimental period, blood was collected for the assessment of serum levels of Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Alkaline phosphatase (ALP), bilirubin, albumin and protein levels. The liver tissue obtained was used for histopathological assessment of liver damage. The levels of ASAT, ALP and Albumin were significantly (p<0.05) increased in the rats administered 2 mg kg-1 but was more (p<0.001) in the 5 mg kg-1 groups. Histopathological studies show vacuolar cytoplasmic degeneration, multiple foci of hepatocyte cloudy swelling and focal areas of hepatocyte necrosis with macrophage infiltration providing supportive evidence for the biochemical analysis with greater toxicity in the groups administered 2 and 5 mg kg-1 of extract. This study demonstrates that the aqueous extract of the stem bark of Sclerocarya birrea extract possess possible hepatotoxic and antihepatotoxic activity at low and high doses, respectively.