Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation(BDPP)rescues impairment ofhippocampus-dependentmemory in amousemodelof sleepdeprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase β-1 (p70S6K). In additional mechanistic studies in vitro, we identified the brain bioavailable phenolic metabolites derived from the metabolismof dietary BDPP that are responsible for the attenuation of SD-mediated memory impairments. On the basis of high-throughput bioavailability studies of brain bioavailablemetabolites after dietaryBDPP treatment,we found that select polyphenol metabolites [e.g., cyanidin-39-O-glucoside and 3-(39-hydroxyphenyl) propionic acid] were able to rescuemTORand p70S6K phosphorylation in primary cortico-hippocampal neuronal cultures, aswell as rescue 4E-BP1 phosphorylation in response to treatment with 4EGI-1, a specific inhibitor of eIF4E-eIF4G interaction. Our findings reveal a previously unknown role for dietary polyphenols in the rescue of SD-mediated memory impairments via mechanisms involving the promotion of protein translation.