Evaluation of prophylactic effects of omeprazole and/or vitamin E on the formation of free oxygen radicals (FOR) and bowel histopathology in the newborn rat model of hypoxia/reoxygenation (H/R) that resembles human necrotizing enterocolitis (NEC). Eighty newborn rats were randomly divided into eight groups. H/R was done using airtight chamber. Rats were exposed to 100% CO2 for 15 min followed by a reoxygenation for the next 15 min with 100% O2. Group 1 (n = 10) was the control group. Group 2 (n = 10) rats received vitamin E. In Group 3 (n = 10) omeprazole was administrated. Group 4 (n = 10) rats received omeprazole and vitamin E. Group 5 (n = 10) rats were subjected to H/R two times for 2 days and one time for 3 days. Group 6 (n = 10) received vitamin E in addition to H/R for 5 days and in Group 7 (n = 10) omeprazole in addition to H/R for 5 days. In Group 8 (n = 10), vitamin E and omeprazole and H/R were applied for 5 days. Rats were killed at the end of the each process and bowel specimens were harvested for histopathological and biochemical investigations. We administrated vitamin E intramuscularly 300 unit/kg per day and omeprazole orally 20 mg/kg per day. Malondialdehyde (MDA), xanthine oxidase (XO), xanthine dehydogenase (XDH) and XO/(XO + XDH) were measured. Vitamin E and/or omeprazole treated rats had significantly less XO% levels than H/R only group (0.36, 0.38 and 0.57, respectively). Similarly, the MDA levels were significantly lower in vitamin E and/or omeprazole received rats than H/R only rats (88.8, 97.9 and 122.6, respectively). All rats treated with omeprazole and/or vitamin E had better biochemical and histopathological levels compared to H/R rats (p < 0.05). Histopathological results show that Group 5 (H/R only) had significantly more intestinal damage when compared with Group 6 (vitamin E + H/R), Group 7 (omeprazole + R/H) and Group 8 (vitamin E + omeprazole + H/R) (p < 0.001). Grade 2 and 3 intestinal damages were only in Group 5 and there were no statistical difference between in Groups 6, 7 and 8 (p > 0.001). Omeprazole and/or vitamin E may protect the biochemical and histopathological intestinal damage of H/R injury in rats. These drugs may be beneficial in the prophylaxis of NEC in humans as well.