Background: Diabetes mellitus (DM) is a chronic metabolic disorder usually complicated by cognitive dysfunction owing mainly to the diabetic-associated oxidative stress. Antox, a multi-antioxidant vitamins compound, is known to exhibit anti-diabetic and neuroprotective properties. Aim of the work: to highlight the possible beneficial effects of Antox in mitigating the histological alterations of the hippocampus in experimentally-induced diabetic rat model as an adjuvant therapeutic preclinical strategy. Material and Methods: Thirty adult male Sprague Dawley rats are randomly allocated into 5 groups that assigned alphabet and treated for 4 weeks. A (Control), B (Diabetic), C (Diabetic/Antox), D (Diabetic/Insulin), and E (Diabetic/Antox/Insulin). At the end of the experimental period, the rats were anesthetized, and the brain samples were excised out and the hippocampus was dissected. Serum glucose and glycosylated haemoglobin (HbA1c) were measured. Also, malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GPX), in addition the expression of TNF-α gene by real-time PCR were measured in hippocampal tissue. Paraffin sections of the hippocampus were processed for staining by H&E and for immunohistochemical analysis of Glial fibrillar acidic protein (GFAP) and P53 immunoreactivity. Results: Diabetic rats have encountered with a remarkable changes in the cytoarchitecture of the hippocampus along with increased serum glucose and HbA1c. In the hippocampal tissue, MDA and expression of GFAP, P53, and TNFα increased, however oxidative enzymes decreased. Antox partially alleviated most deteriorated measurements in the diabetic group compared to the high efficacy effect of insulin. However, Diabetic/Antox/Insulin group has a supreme effect compared with either Antox or insulin groups. Conclusion: Antox elicited an adjuvant role in ameliorating the metabolic and structural changes in the hippocampus via its antioxidant and anti-inflammatory effects. .