Dietary anthocyanins may slow cognitive decline, improve cognitive performance and exert neuroprotective effects against neurodegenerative disorders. However, the underlying mechanisms of their action are not fully understood. This study investigated the effects of 12-week anthocyanin-rich bilberry extract supplementation (0.02%) on global gene expression in the hippocampus of ApoE-/- mice to help the understanding of molecular mechanisms underlying anthocyanin neuroprotective effects. Gene expression analysis identified 1698 differently expressed genes, with 611 downregulated and 1087 upregulated genes. Bioinformatics revealed that these genes regulate different biological processes, including neurogenesis, inflammation, metabolism, cell to cell adhesion, cytoskeleton organization, and Alzheimer's and Parkinson's disease pathology. The bioinformatic analysis also proposed potential miRNAs and transcription factors that could be involved in the mediation of these nutrigenomic effects. Results from molecular docking also suggested that anthocyanins could bind to top transcription factors with, as potential consequence, an impact on their gene expression regulation. Taken together, integrated analysis revealed a multi-target mode of action of anthocyanin-rich bilberry extract in the hippocampus underlying their neuroprotective properties.