Glioblastoma (GBM), the most aggressive grade IV malignant tumor in the central nervous system, presents a poor prognosis. Despite extensive insights into its molecular pathology, the conventional Stupp regimen remains largely ineffective due to several factors, including diffuse tumor infiltration, radioresistance, the blood-brain barrier (BBB), and therapy resistance driven by GBM stem cells (GSCs). Research has established that epigenetic modifications play a crucial role in the initiation, progression, invasion, and treatment resistance of GBM. However, existing epigenetic modulators frequently encounter pharmacokinetic limitations, which significantly compromise their efficacy. As a result, there is an urgent need for novel technologies to enhance the therapeutic impact of epigenetic modulators in GBM. This article reviews and discusses current GBM treatments, with a particular emphasis on the rapidly evolving strategy of nanomedicine. By encapsulating epigenetic modulators in precisely engineered nanocarriers, this approach not only improves drug solubility, stability, and circulation time, but also enhances tumor accumulation through passive or active targeting strategies, while allowing for controlled and intelligent drug release. Importantly, specially designed nanocarrier systems can effectively cross the BBB and overcome drug resistance, paving the way for new drug delivery methods in the management of GBM.