Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach for the effective treatment of cancer. In this paper, we review the role of several natural compounds individually and in combination with chemotherapeutic agents in the treatment of GBM. We also assess the potential of drug delivery approaches such as the Gliadel wafers and role of nanomaterial based drug delivery systems for the effective treatment of GBM.