Abstract: Background and Objective: Cholestasis is a liver disease that occurs when bile flow is restricted or blocked. Estrogen-induced cholestasis is marked by a reduction in bile flow and the accumulation of bile acids in the liver as well as liver damage. The aim was to evaluate the hepatoprotective effect on EE-induced cholestasis in rats of Cranberry Water Extract (CWE). Materials and Methods: Adult albino rats weighing approximately 150±10 g were divided into six groups of six animals each. As control groups, three groups (I, II and IV) and three experimental groups were used (III, V, VI). Results: Oral administration for 15 days of CWE (150 mg kg–1 b.wt.) in EE-treated rats (100 μg kg–1 5 days b.wt.) improved serum cholesterol, bile acid and TBIL as well as hepatic SOD and GPx significantly. Also, CWE inhibited ALP, ALT, γ-GT activity as well as levels of TNF-α, NO, MMP-2 and MMP-9 and MDA in comparison with the EE treatment rats. On the other hand, the liver TLR4, NF-κB and p38MAPK gene expression was down regulated group of rats administrated with cranberry extract when compared with the EE-treated rats. CWE's prophylactic action II is more pronounced than prophylactic one. The hepatoprotective effects of cranberry in restoring normal liver functional ability were also supported by histopathological examination of liver tissues. Conclusion: The results show clearly that cranberry extract has a strong prophylactic effect in EE-induced cholestasis by normalizing the levels of TLR4, NF-κB and p38MAPK gene expression.