Abstract: The present study was designed to evaluate the role of water extract of Nigella sativa on the hypothalamus-pituitary-adrenal axis in alloxan-induced diabetic rats. Forty male white rats were divided into four experimental groups control, diabetic. N. sativa-treated and N. sativa-treated diabetic. At the end of the experimental period (3 weeks), animals in all three groups were fasted for 12 h and blood samples were taken for the determination of glucose levels, serum concentrations of insulin, glucagon, corticosterone and Adrenocorticotropic hormone (ACTH ) in four groups. It was found that water extract of Nigella sativa was investigated for hypoglycemic effect in diabetic rats and induced significant reduction in serum glucose from (19.83±1.25 Mmol L-1) in diabetic group to (9.7±1.10 Mmol L-1) in N. sativa- treated diabetic group. However the blood glucose still higher than the control and N. sativa- treated group, serum insulin increased from (0.54±0.22 Mu L-1) in control group to (0.65±0.06 Mu L-1) in N. sativa –treated group and still higher than control in N. sativa –treated diabetic (0.58±0,06 Mu L-1), serum corticosterone increased in diabetic group (580 ± 22.36 nmol L-1 )compared to control group (311±18.42 nmol L-1) and decreased in N. sativa-treated (238±16.53 nmol L-1) and in N. sativa treated diabetic group (378±19.65 nmol L-1) and still higher than control. Serum Adrenocorticotropic hormone (ACTH) increased in diabetic group (20.72±2.42 pmol L-1 ) compared to control group (13.82±1.83 pmol L-1) and still lower in N. sativa -treated (10.64±13 pmol L-1) and in N. sativa treated diabetic group (15.42±1.18 pmol L-1) compared to diabetic group. The results suggest the beneficial role of N. sativa as hypoglycemic agents and as a protective effect against pancreatic ß-cells damage from alloxan induced diabetes in rats by decreasing oxidative stress and preserving pancreatic ß -cells integrity and also suggest that the antidiabetic effect of N. sativa may be attributed to increased glucose metabolism by increasing the serum concentration of insulin and inhibited the hypothalamus-pituitary-adrenal axis.