In this study the hepatoprotective activity of the crude phenolic rich extract (CPRE) isolated from oyster mushrooms on carbon tetrachloride (CCl4)-induced oxidative stress was investigated in albino rats. The hepatoprotective activity was examined through various biochemical parameters. Administration of CCl4 for 28 days exhibited a significant increase (P<0.05) in serum markers of liver damage, i.e., alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, urea, creatinine, total lipids and triglycerides. Whereas, the serum markers were significantly decreased (P<0.05) by CPRE administration. CCl4 exposure significantly decreased (P<0.05) the hepatic antioxidant enzyme activities such as superoxide dismutase and glutathione peroxidase. Contrarily, the CPRE treatments showed significant increases (P<0.05) in these hepatic activities. The results obtained from this study clearly validated the potential antioxidant activity of CPRE isolated from oyster mushrooms against several oxidation systems in-vivo, which contributed to its hepatoprotective effects in CCl4-induced liver injury in male albino rats. Finally, oyster mushrooms could be added as an additional nutrient to food products as it constitutes a new potential source of natural antioxidant and antibacterial agents.