Dysregulation of immune homeostasis can precipitate chronic inflammation, thus significantly contributing to the onset and progression of metabolic and cardiovascular diseases. Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells that are mobilized in response to biological stressors such as tissue damage and inflammation. Although MDSCs have been extensively characterized in the contexts of cancer and infectious diseases, emerging evidence highlights their pivotal roles in the pathophysiology of metabolic and cardiovascular disorders. We discuss growing evidence for the involvement of MDSCs in the progression of metabolic and cardiovascular diseases, with the aim of deepening our understanding of MDSCs in cardiometabolic physiology and identifying the necessary steps for the development of innovative MDSC-targeted therapeutic strategies.