Many health problems are associated with diabetes. Beta-glucan has been reported to be associated with many health-promoting effects, as it can improve the glycemic index of meals, antioxidant, cholesterol-lowering effect, antibacterial, and control of cancer. This paper aimed to investigate the prophylaxis ability of natural products, β-glucan (βG) Streptozotocin (STZ)-induced diabetic rats. The comparative effectiveness of bacterial and botanical sources of β-glucan on physiological, genetic, and histological responses in diabetic rats was determined. The forty-two Westar rats in the experiment were divided into 7 groups' six rats for each. The 1st served as a control group. The 2nd served as a diabetic group, induced by a single dose of streptozotocin (STZ) (55 mg/kg b.w i.p). The 3rd (Diabetic + Met) treated with M Metformin 90 mg/kg b.w. The 4th (Diabetic + Baβ-GluL) was treated with a low dose of β-glucan from the bacterial source (100 mg/kg b.w.). The 5th (Diabetic + Baβ-GluH) was treated with a high dose of β-glucan from the bacterial source (500 mg/kg b.w.). The 6th (Diabetic + Boβ-GluL) was treated with a low dose of β-glucan from a botanical source (100 mg/kg b.w.). The 7th (Diabetic + Boβ-GluH) was treated with a high dose of β-glucan from the botanical source (500 mg/kg b.w.). Results showed significant pathological alteration for oxide-nitrosative stress markers, lipid profile, neural and hormonal stress parameters, DNA fragmentation, and histopathological alteration in the diabetic group. In contrast, treated groups with a high dose of the β-glucan from a bacterial source or botanical source ameliorated most pathological changes. Nevertheless, a low dose of β-glucan in the bacterial source showed mild amelioration but the low dose of botanical source didn't show any significant amelioration. Data revealed that β-glucan in afforded diabetic rats with prophylactic ability to decrease pathological alteration inflicted by STZ. On the other hand, β-glucan prepared from a bacterial source showed a high affinity for treated diabetic rats from most common symptoms in comparison with a botanical source.