Background: This research evaluates the potential of Alpha lipoic acid (ALA), an antioxidant produced naturally, to protect adult male albino rats' cerebral cortex from the damaging effects of diabetes mellitus. Materials and Methods: 56 adult male albino rats, randomly split up into seven groups, 8 rats in each group. control negative (con-ve) group, control positive group (con+ve), Alpha Lipoic acid (ALA) group, Diabetic (DM) group, Diabetic-Alpha Lipoic acid (DM+ALA) group, Diabetic-Insulin (DM+INS) group, Diabetic-Insulin-ALAacid(DM+INS+ALA) or (DM+COMB.) group. After 4 weeks, blood glucose level, HBA1C, SOD, CAT, IL-1β and MDA in tissue homogenate were estimated. Histopathological procedures applying H & E and Cresyl Violet staining techniques &immunohistochemical procedures using GFAP and synaptophysin antibodies weredone for cortical sections. Results: STZ in DM group induced significant body weight loss, significant elevation of blood glucose, HBA1C, MDA, IL-1β levels, significant decrement in SOD, CAT levels regards control group. Marked disorganization of cortical layers, Pia matter discontinuity and blood vessel congestion, neuropil vacuolation, pyknosis in cortical neurons in H & E stained sections, Sections dyed with Cresyl Violet exhibited karyolysis. An immunohistochemical analysis revealed significant elevation in GFAP expression, and marked decrease of synaptophysin expression. However, these alterations were not as apparent in (DM+ALA) and (DM+INS) groups. In (DM+INS+ALA) there was minimal change in body weight, normalization in blood glucose and HBA1C, significant decrement in MDA and IL-1β levels, significant elevation of SOD, CAT levels compared to DM group. There was a marked improvement in nearly all layers of the cortex insections stained with H & E. In sections stained with Cresyl Violet, Nissl granules were clearly visible and deeply stained. In immunohistochemistry, GFAP expression decreased and synaptophysin expression increased compared to DM group. Conclusion: ALA alone or insulin alone exerted mild or moderate improvement of diabetic changes on the cerebral cortex, but combined ALA and insulin showed marked improvement.