Tribulus terrestris L. has been used in folk medicine throughout history. The present study examined the acute toxicity of the total ethanolic extract of T. Terrestris followed by investigation of the hepatoprotective activity of the total ethanolic extract and different fractions of the aerial parts of the plant compared to silymarin against carbon tetrachloride- induced hepatic damage in rats. In addition, in vivo antioxidant activity was examined and linked to the previous in vitro DPPH free radical scavenging activity investigation. This study established the plant’s safety and the hepatoprotective effect of the total ethanolic extract of the aerial parts of the plant and its different fractions due to significant decrease in CCl4- induced rise in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin in rats. Treatment with the ethyl acetate fraction significantly reduced oxidative stress in CCl4- intoxicated rats, as evident by a decrease in malondialdehyde (MDA) content associated with elevation of hepatic reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hence, this hepatoprotective effect could be due to the antioxidant activity of the plant which is mainly imparted by the two major di-p-coumaroylquinic acid derivatives isolated from the ethyl acetate fraction.