Cancer cells “hijack” host immune cells to promote growth, survival, and metastasis. The immune microenvironment of high-grade gliomas (HGG) is a complex and heterogeneous system, consisting of diverse cell types such as microglia, bone marrow-derived macrophages (BMDMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, natural killer (NK) cells, and T-cells. Of these, MDSCs are one of the major tumor-infiltrating immune cells and are correlated not only with overall worse prognosis but also poor clinical outcomes. Upon entry from the bone marrow into the peripheral blood, spleen, as well as in tumor microenvironment (TME) in HGG patients, MDSCs deploy an array of mechanisms to perform their immune and non-immune suppressive functions. Here, we highlight the origin, function, and characterization of MDSCs and how they are recruited and metabolically reprogrammed in HGG. Furthermore, we discuss the mechanisms by which MDSCs contribute to immunosuppression and resistance to current therapies. Finally, we conclude by summarizing the emerging approaches for targeting MDSCs alone as a monotherapy or in combination with other standard-of-care therapies to improve the current treatment of high-grade glioma patients.