Diabetes results in various complications and 90% of all diabetic cases suffer from type-II diabetes (T2D). Therefore, there is a need to find novel interventions that can protect from diabetic complications and reduce the side effects of currently used antidiabetic drugs. We examined the anti-diabetic effect of Curcumin-Magnesium oxide nanoparticles conjugate (Cur-MgO NPs conj) in streptozotocin (STZ)-induced T2D in male rats while considering hematologic, immunologic, and hepatic metabolic responses. The study included three groups: group 1 (control group), group 2 (STZ-induced T2D), and group 3 (STZ-induced T2D in rats that were orally administered with Cur-MgO NPs conj (5mg/Kg/day for 45 days). Complete blood count, levels of plasma glucose, serum insulin, lipid profile, and hepatic expression of the lipogenic enzymes, namely acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were measured. Histopathological examination of spleen was also conducted. Compared to the control group, a significant elevation in blood glucose and homeostatic model assessment- insulin resistance (HOMA-IR), a substantial reduction in serum insulin level and HOMA-β, an upregulation in hepatic mRNA expression of fatty acid synthase (FAS) and acetyl-CoA carboxylases (ACC), and an altered lipid profile were noticed in STZ-induced T2D group. Oral administration of Cur-MgO NPs conj restored some of the parameters to their physiological levels, including glucose, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c). Histopathological examination of the spleen showed abnormalities in lymphoid cells in T2D, while the treated group showed moderate improvement in spleen tissue, and cells were rescued from apoptosis. The data of this study revealed that Cur-MgO NP conj has a potential ameliorative effect on the hematologic, immunologic, and hepatic metabolic alterations in STZ-induced T2D in rats.