Long-term high-fat diet (HFD) in rats triggered cerebral oxidative stress, reflected by reactive oxygen species accumulation and antioxidant decline in peripheral and cerebral tissues, together with hippocampal lipid disturbance, particularly for triglyceride accumulation and sulfatide deficiency. Hippocampal formation and cerebral cortex also exhibited pathological changes, characterized by neurofibrillary tangle and reduced Nissl bodies. Sulfatides were noted to protect hippocampal neurons from oxidative damage through the clearance of β-amyloid protein, with apolipoprotein E transporting and low-density lipoprotein receptor binding. Delightedly, we found γ-aminobutyric acid (GABA) supplement delivered by rice bran to rats significantly promoted hippocampal sulfatide synthesis and reversed the HFD-induced sulfatide deficiency and oxidative-triggered cerebral impairment. Elevated GABA concentration in hippocampus and the activation of GABA B-type receptors might be the primary contributors. This study demonstrated the potential of GABA-enriched rice bran as a novel dietary supplement to enhance a sulfatide-based therapeutic approach for neurodegenerative diseases in the early stages.