Polyphenols are metabolites derived from plant-based sources studied in cancer research for their anti-inflammatory, antioxidant, and antiproliferative properties. While previous studies have focused more on their impact on gastrointestinal diseases like inflammatory bowel disease and malignancies such as colon cancer, there is less attention on their role in neurological diseases and malignancies more distant from the gastrointestinal tract, like brain cancer. Recent work indicates potential for polyphenols to beneficially modulate the gut microbiome and improve neurological disorders through the gut-brain axis. Glioblastoma (GBM), classified as a grade 4 brain tumor by the World Health Organization, poses significant challenges with inefficient conventional treatments that yield a low five-year survival rate. Recent meta-analyses demonstrate the potential of various plant foods to reduce the risk of glioma. However, specific dietary recommendations for brain cancer remain elusive, and the mechanisms of action of plant foods and their compounds, as well as their impact through the gut-brain axis, must still be explored. This review will discuss the impact of polyphenols on the gut-brain axis and analyze the potential benefits of implementing them as preventive and therapeutic GBM interventions with relation to the gut microbiome.