Cerebral oxidative stress and inflammation play an important role in the pathophysiology of diabetes-related cognitive impairment. Therefore, the peptide-rich mixture from wheat bran (EHWB) was adopted to investigate its neuroprotective effect on H₂O₂-damaged SH-SY5Y cells and diabetic rats. Results showed that pre-incubation of EHWB alleviated oxidative stress in H₂O₂-damaged SH-SY5Y cells by increasing levels of superoxide dismutase, glutathione, brain-derived neurotrophic factor, and reducing the generation of reactive oxygen species. Furthermore, EHWB pretreatment improved cell cycle arrest in the G2/M phase. More importantly, this study, at least in part, confirmed that EHWB could penetrate through the blood-brain barrier to exert a neuroprotective effect through an in vitro transwell model. EHWB administration improved the behavior performance in diabetic rats, including explorative activities, spatial learning and memory. Particularly, this study found that EHWB markedly suppressed the astrocyte activation, as shown by the downregulation of glial fibrillary acidic protein in the cornu ammonis 1 region of the hippocampus, but not for other regions or microglia. The potential mechanism of cognition enhancement of EHWB might be related to the signaling cascades induced by brain-derived neurotrophic factor (BDNF) via the BDNF/tropomyosin-related kinase receptor B (TrkB)/cAMP response element binding protein (CREB) pathway. This study might highlight a new ingredient for the prevention and protection of cognitive dysfunction.