Glioblastoma multiforme (GBM) represents the most common and fatal form of primary invasive brain tumors as it affects a great number of patients each year and has a median overall survival of approximately 14.6 months after diagnosis. Despite intensive treatment, almost all patients with GBM experience recurrence, and their 5-year survival rate is approximately 5%. At present, the main clinical treatment strategy includes surgical resection, radiotherapy, and chemotherapy. However, tumor heterogeneity, blood-brain barrier, glioma stem cells, and DNA damage repair mechanisms hinder efficient GBM treatment. The emergence of nanometer-scale diagnostic and therapeutic approaches in cancer medicine due to the establishment of nanotechnology provides novel and promising tools that will allow us to overcome these difficulties. This review summarizes the application and recent progress in nanotechnology-based monotherapies (e.g., chemotherapy) and combination cancer treatment strategies (chemotherapy-based combined cancer therapy) for GBM and describes the synergistic enhancement between these combination therapies as well as the current standard therapy for brain cancer and its deficiencies. These combination therapies that can reduce individual drug-related toxicities and significantly enhance therapeutic efficiency have recently undergone rapid development. The mechanisms underlying these different nanotechnology-based therapies as well as the application of nanotechnology in GBM (e.g., in photodynamic therapy and chemodynamic therapy) have been systematically summarized here in an attempt to review recent developments and to identify promising directions for future research. This review provides novel and clinically significant insights and directions for the treatment of GBM, which is of great clinical importance. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.