The acetaminophen is one of analgesic; non-steroidal anti-inflammatory drugs can cause the hepatotoxicity. Many of the hepatoprotective of plant use in medicine to treatment of hepatic disorders. The aqueous Capparis spinosa extract (CSE) (500 mg/kg) was used to reduce the hepatotoxicity induced by paracetamol (PARA) (300mg/kg). The current study, 70 male albino mice (25-30 g) were divided into five group; group I: It were received 0.9% sodium chloride (control), group II: It were given PARA intraperitoneally (IP) (300 mg/kg), single dose, group III: It were received PARA as a single dose (300 mg/kg) intraperitoneally (IP) directly followed by oral administration of the CSE (500 mg/kg) single dose per day for 21 days, group IV: It were received CSE (500 mg/kg) single dose per days for 21 days the injected by PARA intraperitoneally (IP) (300mg/kg), and Group V: It were administered orally of CSE only (500 mg/kg) per days for 21 days. The animals each groups above sacrificed at 1 h, 6h, 12h, 24h, 72h, 10 days and 21 days. Blood samples were collected to determine the serum of CYP450 2E1 and GSH. The PARA (300mg/kg) increased the CYP450 2E1 and reduced the GSH serum levels significantly when compared with the control group (P<0.05). The CSE showed non-significantly effect on these markers. The CSE showed the higher reducing effect on CYP450 2E1 and GSH level induced by PARA toxicity about 19.53% in (CSE+PARA) group, and about 62.52% in (PARA+CSE) group respectively. This research conclude that the CSE (500 mg/kg) reduces the hepatotoxicity of paracetamol (300mg/kg IP) significantly.