Anthocyanin-rich diet can preserve cognitive decline and prevent or delay the development of neurogenerative disorders. It has been shown that an increase in blood-brain barrier permeability, regulated by brain endothelial cells, is the key factor in the development of these disorders. However, cellular and molecular mechanisms of anthocyanins on brain endothelial cells are still unknown. The aim of this study was to identify the capacity of anthocyanins to prevent an inflammatory-induced increase in brain endothelial cell permeability and decipher the in-depth underlying molecular mechanism of action using a multi-genomic approach. Human brain microvascular endothelial cells (HBMEC) were exposed to mixture of anthocyanins or mixture of gut microbiome-derived metabolites (GMDM) prior to the induction of an inflammatory stress using TNF alpha. The effects on adhesion of immune cells to HBMEC and their permeability to immune cells were assessed in vitro. Total RNA was extracted and global gene expression analyzed using genomic microarrays followed by in-depth bioinformatic analysis. We observed that anthocyanins as well as GMDM can reduce the inflammatory-induced adhesion of monocytes to endothelial cells and decrease HBMEC permeability to immune cells. These effects were associated with the capacity of anthocyanin metabolites to modulate the global expression of protein-coding genes but also non-coding genes, including miRNAs, lncRNAs and snoRNAs. Bioinformatic analysis showed that these genes and target genes of non-coding RNAs are involved in the regulation of cell-cell interactions, cytoskeleton organization, focal adhesion, and chemotaxis. In-silico docking analysis showed that these metabolites can interact with transcription factors and cell signaling proteins involved in the regulation of observed DEGs. Global genomic profile was observed to be inversely correlated with genomic modifications reported in patients with neurodegenerative disorders. In conclusion, anthocyanin metabolites can prevent inflammation-induced blood-brain barrier permeability by maintaining endothelial cell functions through multi-genomic modes of action. These cellular and molecular mechanisms could underlie the neurocognitive protective properties of dietary anthocyanins.