The aging of populations worldwide is driving greater demands for dietary polyphenols which have been recognized as promising prophylactic and/or therapeutic agents in the context of neurodegeneration, and are ubiquitously present in plant-based diets. In particular, grape-derived products encompass a wide array of phenolic compounds purported with multiple health benefits including neuroprotective efficacy. Despite the increasing preclinical and clinical evidence demonstrating high potential of grape polyphenol (GPP)-rich botanicals in preventing and attenuating diverse neurodegenerative disorders, the limited bioavailability of GPPs, especially in the brain, generates questions as to their applications and effectiveness in neuroprotection. To address this issue, significant research efforts have been made to enhance oral bioavailability of GPPs via application of novel strategies. This review highlights some critical issues related to the bioavailability and neuroprotective efficacy of GPPs and GPP-rich botanicals. The representative bioavailability-enhancing strategies are critically reviewed to provide practical solutions for augmenting the bioefficacy of GPP-rich botanicals. Synergistic applications of encapsulation techniques (for physiochemical protection and bypassing xenobiotic metabolism) and dietary intervention strategies involving modulation of gut microbiota (for generating more bioavailable phenolic metabolites) appear promising, and may substantially enhance the bioefficacy, especially the neuroprotective efficacy, of orally consumed GPPs.