A systematic analysis of the root bark of Zanthoxylum chalybeum was conducted to establish the antidiabetic potential of isolated compounds based on its ethnomedicinal use to manage diabetes. Chromatographic separation of alkaloid extracts led to isolation of three undescribed amides, chaylbemide A (1), chalybemide B (2) and chalybemide C (3) alongside the known fagaramide (4); four known benzophenanthridine alkaloids skimmianine (5), norchelerythrine (6), 6-acetonyldihydrochelerythrine (7) and 6-hydroxy-N-methyl decarine (8). The alkaloid free extracts yielded three known lignans, ailanthoidol (9), 2,3-epoxy-6,7-methylenedioxy coniferyl alcohol (10), sesamine (11), together with five known triterpenoids, lupeol (12), lupanone (13), 3alpha,20-dihydroxy-28-lupanoic acid (14), 20-hydroxy-3-oxo-28-lupanoic acid (15) and 3alpha,20,28-trihydroxylupane (16). The structures of the compounds were established based on 1D and 2D NMR spectroscopic and mass spectrometric experiments. Compounds 1-8 displayed inhibitory activities against both alpha-amylase and alpha-glycosidase in the range of IC(50) = 43.22-49.36 muM which showed no significant (P > 0.05) difference to the positive control acarbose (IC(50) = 42.67; 44.88 muM). The results confirmed anti-hyperglycemic potential of alkaloids from Z. chalybeum which lends credence to its use towards management of diabetes susceptibilities. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved.