Diabetes mellitus is increasingly recognised as a contributor to neurodegeneration through oxidative stress, chronic inflammation, and protein glycation within the brain. Calcitriol - the active form of vitamin D - is postulated to target these molecular disturbances, but its neuroprotective potential remains poorly understood. This study investigated the effects of calcitriol on neuroinflammatory responses, glycooxidative damage, and intracellular signaling within two anatomically distinct brain regions - the hypothalamus and cerebral cortex - in a rat model of type 2 diabetes. Male Wistar rats were assigned to three groups: control, diabetes, and diabetes treated with calcitriol. Type 2 diabetes was induced using a high-fat diet followed by streptozotocin administration at week 4, while calcitriol was given orally at 0.1 μg/kg for eight weeks. Multiplex immunoassays and biochemical analyses were used to evaluate cytokines, chemokines, lipid and protein oxidation products, and signaling proteins associated with metabolic and neurodegenerative pathways. Diabetic rats exhibited metabolic dysfunction, pronounced neuroinflammation, increased lipid and protein glycooxidation, mitochondrial impairment, and dysregulation of apoptosis- and insulin-related signaling. Calcitriol significantly improved systemic metabolic indices and attenuated pro-inflammatory cytokine and chemokine profiles, reduced advanced glycation end products, malondialdehyde, and protein carbonyls, and partially restored mitochondrial and intracellular signaling homeostasis. Notably, the hypothalamus exhibited a stronger response to calcitriol than the cerebral cortex, suggesting region-specific neuroprotective effects. These findings indicate that calcitriol may represent a promising therapeutic strategy for mitigating type 2 diabetes-related neurodegeneration by targeting oxidative stress, glycation, and inflammatory signaling within the brain.