Glioblastoma is the most destructive type of malignant brain tumor in humans due to cancer relapse. Latest studies have indicated that cancer cells are more reliant on autophagy for survival than non-cancer cells. Autophagy is entitled as programmed cell death type II and studies imply that it is a comeback of cancer cells to innumerable anti-cancer therapies. To diminish the adverse consequences of chemotherapeutics, numerous herbs of natural origin have been retained in cancer treatments. Additionally, autophagy induction occurs via their tumor suppressive actions that could cause cell senescence and increase apoptosis-independent cell death. However, most of the drugs have poor solubility and thus nano drug delivery systems possess excessive potential to improve the aqueous solubility and bioavailability of encapsulated drugs. There is a pronounced need for more therapies for glioblastoma treatment and hereby, the fundamental mechanisms of natural autophagy modulators in glioblastoma are prudently reviewed in this article.