Simple SummaryGlioblastoma’s poor prognosis calls for the discovery of newer, more efficacious management and treatment methods. This review collates and examines how the antidiabetic drug metformin and nonflavonoid polyphenol resveratrol, a dietary supplement with antidiabetic effects, can complement current treatment methods. Specifically, metformin and resveratrol exert anticancer effects on major metabolic pathways in glioblastoma cells, resulting in reduced proliferation, increased apoptosis, and reduced tumor growth and volume. The shown effects suggest that metformin and resveratrol can potentially aid in treating glioblastoma. The novel delivery methods and a lack of clinical studies endorse further clinical investigations.AbstractGlioblastoma, a malignant brain tumor, is a common primary brain tumor in adults, with diabetes mellitus being a crucial risk factor. This review examines how the antidiabetic drug metformin and dietary supplement resveratrol can benefit the treatment of glioblastoma. Metformin and resveratrol have demonstrated action against relevant pathways in cancer cells. Metformin and resveratrol inhibit cell proliferation by downregulating the PI3K/Akt pathway, activating mTOR, and increasing AMPK phosphorylation, resulting in lower proliferation and higher apoptosis levels. Metformin and resveratrol both upregulate and inhibit different cascades in the MAPK pathway. In vivo, the drugs reduced tumor growth and volume. These actions show how metformin and resveratrol can combat cancer with both glucose-dependent and glucose-independent effects. The pre-clinical results, alongside the lack of clinical studies and the rise in novel delivery mechanisms, warrant further clinical investigations into the applications of metformin and resveratrol as both separate and as a combination complement to current glioblastoma therapies.