HOX (homeobox) genes are virtually absent in healthy adult brains but are detected in malignant brain tumors, particularly gliomas. In 2021, the World Health Organization (WHO) classified adult-type diffuse gliomas into three distinct categories: astrocytomas (isocitrate dehydrogenase [IDH]-mutated), oligodendrogliomas (IDH-mutated and 1p/19q-deleted), and glioblastomas, IDH-wildtype (GBM). GBM is the most common and aggressive primary malignant tumor of the Central Nervous System (CNS), characterized by its high recurrence rate and rapid growth. Dysregulation of HOX genes is a well-established phenomenon in both solid and liquid malignancies, playing crucial roles in various fundamental characteristics of cancer, including GBM. In recent years, HOX genes have gained recognition not only as key regulators of tumor progression but also as potential biomarkers for predicting disease outcomes and as promising therapeutic targets for GBM. This review compiles the latest research on HOX genes in GBM, encompassing studies published before and after the 2021 WHO classification of CNS tumors. Our goal is to provide a comprehensive overview of key findings on the role of HOX gene clusters, which are groups of genes involved in regulating the development of the body plan along the anterior-posterior axis, in GBM initiation, progression, prognosis, and treatment response.