Diabetes mellitus is a chronic metabolic disease that is caused by a relative lack of insulin and/or reduced insulin activity resulting in hyperglycaemia. The rise in poverty level coupled with side effects of available anti-diabetic drugs necessitated the evaluation of a medicinal plant, Chrysophyllum albidum, claimed to be used in the management of diabetes. The objectives of the study were to: (i) evaluate the anti-diabetic activity of aqueous extract of C. albidum stem bark (AECASB); (ii) carry out solvent partitioning of AECASB and evaluate their anti-diabetic activity; (iii) carry out bioactivity-guided chromatographic fractionation (CF) of the most effective solvent-partitioned fraction (SPF) of AECASB and evaluate their anti-diabetic activity; (iv) identify the bioactive principles in the most effective CF of AECASB; (v) carry out safety evaluation of the antidiabetic principle(s)-rich CF of AECASB and (vi) propose the mechanism of action of the antidiabetic principle(s)-rich CF of AECASB.rnA total of 340 female rats (180.80 Â± 8.50g) were assigned into group A (received 1.0 ml of distilled water) while the diabetic rats {induced by intraperitoneal administration of 120 mg/kg body weight (bw) of alloxan} in groups B, C, D, E, F, G were orally administered distilled water, glibenclamide (reference antidiabetic drug), 25, 50, 100 and 200 mg/kg bw of AECASB respectively, once daily for 14 days. Crude, SPFs (ethyl acetate, residue, n-butanol)andCF (1-10) were also screened. Biochemical assessments and histological examinations were also carried out. Data were analysed with Analysis of Variance and Tukeyâ€™s post-hoc test at p < 0.05.rnThe findings in this study revealed that:rni. AECASB reversed the alloxan treatment related increases in fasting blood glucose (FBG), serum urea, creatinine, hepatic glucose (HG), amylase activity and related decreases in albumin, glycogen, erythrocytic indices, glucokinase (GK) and glucokinase-6-phosphate dehydrogenase (G6PDH) activities. rnii. AECASB also restored the deranged histoarchitecture of the pancreas caused by alloxan;rniii. ethyl acetate-partitioned fraction reduced (p<0.05) FBG, HG, Î±-amylase activity, total cholesterol, triglycerides, malondialdehyde (MDA), ameliorated the obliteration observed in pancreas due to alloxan treatment while glycogen, high density lipoprotein (HDL), G6PDH, SOD and catalase activities increased significantly (p<0.05);rniv. Chromatographic fractions F5 and F7 decreased (p<0.05) FBG, HG, organ body-weight ratio, glycosylated haemoglobin, C-reactive protein, glucose-6-phosphatase and fructose-1,6-bisphosphatase activities, TC, triglycerides, atherogenic index, MDA while BW, serum insulin, glycogen, HDL, GK, G6PDH, catalase, SOD activities significantly (p<0.05) increased;rnv. procyanidin,stigmasterol, catechin, epicatechin, epigallocatechin,hexadecane,eleagnine, octadecanoic acid and eicosane were detected in F7;rnvi. CFs 5 and 7 did not alter urea, creatinine, albumin, bilirubin, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase activities;rnvii. catechin, stigmasterol and procyanidin B5 are the likely bioactive principles in CF7; and rnviii. mode of anti-diabetic action of AECASB and F7 may be via regenerating the pancreas and enhancing the activities of glucose metabolising and antioxidant enzymes.rnThe study concluded that CF7 produced the most profound anti-diabetic activity and is relatively safe. AECASB can be explored as lead drug for the management of diabetes.