Diabetes Mellitus (DM) is a progressive metabolic disorder of carbohydrates and lipids that is characterized by hyperglycemia. 1 DM is known to result from defect in insulin secretion, action or both. 2 Poor management of diabetes mellitus can degenerate into debilitating conditions including heart attack, stroke, kidney failure, leg amputation, vision loss, nerve damage and erectile dysfunction. 1 The inability of the cells to assimilate glucose formed via stepwise catabolism of carbohydrates with α-amylase and α-glucosidase, leads to hyperglycemia. Likewise, hyperactivity of pancreatic lipase results to increase in lipid metabolism which also triggers hyperlipidemia. 3-4 Therefore, hyperglycemia and hyperlipidemia continue to be the underlying factors in the onset of diabetes mellitus and its complications. 5 In addition, reactive oxygen species also play crucial role in the pathogenesis of diabetes mellitus. 6 Despite the potency of currently used diabetic drugs such as acarbose, Voglibose, Miglitol, insulin mimetics and secretagogues, they still are associated with adverse side effects. 7 Therefore, the search for alternative In-vitro Anti-diabetic and Antioxidant Efficacy of Methanolic Extract of Encephalartos ferox leaves ABSTRACT Background: Diabetes mellitus has been identified as one of the global cause of disability and death. Objectives: The study aim to investigate the in-vitro antidibetic and antioxidant activities of methanolic extract of Encephalartos ferox leaves. Materials and Methods: The plant was screened for its Phytochemical composition. The plant material was extracted with methanol and the methanolic extract was screened (in-vitro) for its antioxidant activity using ABTS and DPPH assays. The potential antidiabetic activity of the plant extract was evaluated against some carbohydrates (α-amylase and α-glucosidase) and lipid (pancreatic lipase) digestive enzymes. The inverted intestinal sac model was also used to investigate the effect of the extract on intestinal glucose absorption. The anti-protein glycation activity of the extract was determined using haemoglobin. Results: The phytochemical screening revealed the presence of most of the phytochemicals (Tannins, Flavonoids, Terpenoids, Alkaloids etc) that were screened for. The crude extract exhibited the antidiabetic potential as it significantly (P < 0.05) inhibited α-glucosidase and pancreatic lipase in a dose dependent fashion. The extract also effectively reduced intestinal glucose absorption. The extract further showed antioxidant activity by efficiently scavenging ABTS and DPPH radicals with IC 50 values of 68.3 µg/ml and 308 µg/ml, respectively. The extract also inhibited haemoglobin glycation, thus displaying the anti-protein glycation potential. Conclusion: It is apparent that E. ferox extract could serve as scaffold for diabetic therapy. For future study, cytotoxicity profile and in vivo investigation of the antidiabetic activity of the crude extract are essential.