<p>Glioblastoma Multiforme is an aggressive and complex cancer affecting mostly elderly patients above the age of 60&#xa0;years. Originally classified as the fourth stage of glioma, it has an abysmal prognosis along with limited therapeutic options. Surgical removal of tumors, radiotherapy, and chemotherapy are prevalent treatment strategies with numerous therapeutic obstacles, including undefined boundary of tumor mass leaving traces even after excision, chances of secondary cancer formation, and presence of blood–brain barrier. These blood–brain and blood–brain tumor barriers actively restrict the permeability of many molecules from blood circulation to enter the central nervous system. Therefore, many conventional antineoplastic drugs fail to reach the tumor periphery except temozolomide. Meanwhile, active stem cells in the tumor microenvironment, genetic mutation inducing tumor growth, and epigenetic pattern alteration make this cancer chemoresistant. Our review delineates the recent approaches to resensitize the existing clinical drugs through specifically designed nanoformulations. Nanoparticles with modified physiological characteristics and modified through technological parameters can reduce the tumor's stemness, which increases tumor cells' apoptosis rate. Moreover, these nanoparticles can efficiently traverse the blood–brain barrier and escape from endosomal degradation with minimum toxicological impact. Overall, this review discusses the cancer chemoresistance phenomena and related pathways and highlights the potential of nanoformulation in reversing chemoresistance. Also, the existing limitations of this unique approach and suggestions are discussed at the end of the article, which may facilitate the identification of new directions for advancement of the nanoparticle-mediated reversal of chemoresistance.</p> Graphical Abstract <p></p>