Impairment in glucose regulation is an indicatory effect capable of mediating multiple dysfunction such as cerebrovascular disorder with ischemia and brain damage inclusive. This study aims at investigating the glucoselowering and neuroprotective capability of Diosgenin (DG) towards hyperglycemia-induced cerebral injury in a developed type 2 diabetes mellitus (T2DM) Zebrafish (ZF) model. T2DM was developed in ZF with 20 mg/kg body weight (b.w) multiple-low dose (MLD) Streptozotocin (STZ) for 28 days. Different doses of 20 mg/kg b.w (DG1) and 40 mg/kg b.w (DG2) DG was intraperitoneally administered twice in 7 days for a period of 28 days after T2DM was completely developed. Weight and behavioral changes were monitored and the catalytic activity including the plasma glucose level of diseased and treated ZF was spectrometrically estimated. Histopathological studies were employed to image the brain pathological condition during disease and treatment. SPSS was used as the statistical tool for result analysis and comparison of data obtained. STZ significantly ( ### p < 0.001) induced hyperglycemia when compared to control as plasma glucose increases from 101.56 AE 4.52 mgdL À1 to 175.87 AE 6.00 mg/dL. Our results have indicated a marked reduction in glucose concentration from a mean average of 175.87 AE 6.00 mgdL À1 to 105.68 AE 4.48 mgdL À1 and 82.06 AE 7.27 mgdL À1 in DG 1 and DG 2 respectively. Catalytic activity significantly decreases (p < 0.05) from 206.42 AE 30.77 unit/mL to 123.85 AE 29.99 unit/mL at a minimum and maximum value of 103.21 and 275.23 in diseased ZF respectively. On DG treatment, catalytic activity significantly (p < 0.01) rise from 101. 58 AE 11.29 and 130.73 AE 27.52 to 130.98 AE 17.13 and 255.96 AE 30.34 with DG1 and DG2 treatment respectively. Studies on the behavioral pattern of STZ-induced anxiolytic effect on ZF confirmed changes in the number of transitions and time spent in both Novel tank test (NTT) and Dark/light test (LDT). Histopathological analysis confirmed the cerebral cortex with inflammatory brain cells in the diseased condition and an attenuation of damage posed revealed in diseased state was largely reversed with DG. As compared to the normal control, a significant ( # p < 0.05 and ### p < 0.001) changes in weight of fishes were recorded and DG1 and DG2 significantly promotes (***p < 0.001) body weight and improves the irregularities in weight of ZF during disease progression. Our study confirms that the potential of DG towards the management of hyperglycemia and hyperglycemia-mediated cerebral ischemic injury is through its blood glucose-lowering properties, anti-inflammatory activity, antioxidant effect, and anxiolytic capabilities.