Unhealthy diets are associated with various diseases that can disrupt brain energy metabolism, which significantly increased the risk of cognitive impairment and chronic neurodegenerative diseases. Early intervention with nutritional supplements may have long-lasting positive effects on diet-related glucose metabolism and potentially mediate the progression of neurodegeneration in middle-aged and elderly people. We previously reported that cyanidin 3-O-β-galactoside (Cy3Gal), an anthocyanin from black chokeberry (Aronia melanocarpa (Michx.) Elliott), alleviated cognitive impairment in aging mice through regulating brain energy metabolism. However, it remains unclear whether Cy3Gal can also exert beneficial effects in mice fed with a high-fat/high-sugar diet. Here we revealed that Cy3Gal treatment conserved the health of neurons and synapses, as well as cognitive function of mice. Furthermore, we observed that Cy3Gal effectively improved glucose uptake and metabolism of skeletal muscle by enhancing glycolysis both in vivo and in vitro models, which is essential for maintaining a stable glucose supply to the brain. Additionally, Cy3Gal significantly increased the levels of glucose-derived tricarboxylic acid cycle intermediates in the mice brain (P < 0.05), and regulated the activities of mitochondrial respiratory chain complexes (P < 0.01). The positive influence on peripheral and brain bioenergetics explained how the Cy3Gal exerted neuroprotective effect. In conclusion, our study illustrated that early dietary intervention of Cy3Gal had significant advantages in terms of neuroprotection and cognition under the challenge of HFHS diet-induced glucose metabolism disorder.