Glioblastoma (GBM) remains a formidable challenge in neuro-oncology due to its aggressive nature and propensity for therapeutic resistance. Anti-vascular endothelial growth factor (VEGF) therapies, although promising, often encounter resistance that limits their clinical efficacy. A multi-target and multi-drug approach has emerged as compelling strategies to address this resistance to enhance the treatment outcomes. This review examines the complex environment of anti-VEGF resistant GBM and analyses a multi-target therapeutic approach using natural products.