Introduction: This study examines the potential of Alpha lipoic acid (ALA), a natural antioxidant, in safeguarding the cerebral cortex of adult male albino rats against the harmful impacts of diabetes mellitus. Materials and Methods: The research involved 56 adult male albino rats split up into seven groups, each comprising 8 rats: control negative (con-ve), control positive (con+ve), Alpha Lipoic acid (ALA), Diabetic (DM), Diabetic-Alpha Lipoic acid (DM+ALA), Diabetic-Insulin (DM+INS), and Diabetic-Insulin-ALA (DM+INS+ALA) or (DM+COMB.) group. After a 4-week period, various parameters including blood glucose levels, HbA1c, SOD, CAT, IL-1β, and MDA in tissue homogenate were assessed. Histopathological techniques like H & E and Cresyl Violet staining, along with immunohistochemical procedures using GFAP and synaptophysin antibodies, were carried out on cortical sections. Results: In the DM group, there was notable weight loss, significant increased blood glucose, HbA1c, MDA, IL-1β, significant decreased SOD and CAT levels compared to control group. Cortical disorganization, pia matter discontinuity, blood vessel congestion, neuropil vacuolation, and pyknosis were observed in H & E stained sections. Cresyl Violet staining showed karyolysis. GFAP expression rose significantly, while synaptophysin expression dropped markedly. These changes were less pronounced in the DM+ALA and DM+INS groups. DM+INS+ALA group showed minimal weight change, normalized blood glucose and HbA1c, significant reduced MDA and IL-1β, and significant increased SOD and CAT levels compared to DM. Cortical layers improved visibly in H & E sections. Cresyl Violet staining revealed distinct deeply stained Nissl granules. Immunohistochemistry indicated decreased GFAP and increased synaptophysin expressions compared to DM. Conclusion: While ALA or insulin alone demonstrated mild to moderate improvements in diabetic changes within the cerebral cortex, the combined ALA and insulin treatment displayed significant enhancement in mitigating these effects.