Objective: Setaria megaphylla (Steud) Dur & Schinz (Poaceae), a perennial grass used traditionally in the treatment of various diseases including diabetes was evaluated for effect on alpha amylase and alpha glucosidase enzymes. Materials and methods: The leaf fractions (hexane, dichloromethane, ethyl acetate, methanol, 200 mg/kg) of Setaria megaphylla in vivo were evaluated for inhibitory effect on alpha amylase and alpha glucosidase enzymes using starch, sucrose and maltose as substrates. Acarbose was used as referenced drug.The leaf fractions Results: caused significant (p<0.05) reduction in blood glucose levels of treated with the various substrates used. -hexane n fraction exerted the highest inhibitory effect when starch and sucrose were used as substrates followed by methanol. Methanol was the most active fraction followed by hexane when maltose was used as substrate. The results suggest that the leaf fractions of have the potentials to inhibit alpha amylase and glucosidases in rats.