This study was carried out to investigate the hepatoprotective effect of deut erium depleted water (DDW) with and without Satureja rechingeri essential oil (E.O) mixture on paracetamol induced hepatotoxicity in rats. The animals were divided into 24 groups (n=5): The negative control group used tap water in 14 days following DMS O i.p injection at day 15th. The control group received tap water in 14 days following 500 mg/kg b.w. i.p injection of acetaminophen dissolved in DMSO. The treatment groups received only DDW (30 and 60 ppm) in 14 days concomitant with treatment groups receiving DDW plus i.p injection of S. rechingeri oil following acetaminophen injection at day 15th. Indeed, hepatoprotective activity was evaluated by the biochemical estimation of acetaminophen metabolism enzymes; cytochrome P450(CYP450), glutathione s-transferase (GST) together with the level of glutathione (GSH). The markers of liver injuries (ALT, AST, and ALP ) were also estimated in plasma. The results indicated that administration of DDW and DDW+E.O resulted in liver damage compensation as manifested by significant decrease in the activities of CYP450 and AST as well as significantly elevating the levels of GSH and GST. The present study reveals that the DDW could afford a significant protection against paracetamol? induced hepatocellular injuries.