Ziziphus mauritiana Lamk. (Rhamnaceae) is a fruit tree that has been used as folkloric medicine for many ailments and diseases. In the present study, the hypoglycemic effect of seed extract of Ziziphus mauritiana in alloxan-induced diabetic mice was assessed. Seed extract was administered orally at doses of 100, 400, and 800 mg/kg body weight (bw) and also in combination with glyburide (800 mg/kg seed extract and 10 mg/kg glyburide) to different groups of mice (normal and alloxan-treated diabetic mice). Their blood glucose level (in acute and sub-acute study), body weight, and mortality rate were monitored. Oral glucose tolerance test (OGTT) was also performed. Oral administration of extract alone or in combination with glyburide reduced the blood glucose level in all the diabetic mice after acute and sub-acute (28 days) administration. Administration of the extract reduced the weight loss and mortality rate during the sub-acute study. The results of blood glucose level, loss in body weight, and mortality rate were more pronounced in the group treated with combination (800 mg/kg seed extract and 10 mg/kg glyburide). The extract also augmented the glucose tolerance in both normal and diabetic mice. These results suggest that the extract possesses synergistic hypoglycemic activity.