The expansion of myeloid-derived suppressor cells (MDSCs), known as heterogeneous population of immature myeloid cells, is enhanced during several pathological conditions such as inflammatory or viral respiratory infections. It seems that the way MDSCs behave in infection depends on the type and the virulence mechanisms of the invader pathogen, the disease stage, and the infection-related pathology. Increasing evidence showing that in correlation with the severity of the disease, MDSCs are accumulated in COVID-19 patients, in particular in those at severe stages of the disease or ICU patients, contributing to pathogenesis of SARS-CoV2 infection. Based on the involved subsets, MDSCs delay the clearance of the virus through inhibiting T-cell proliferation and responses by employing various mechanisms such as inducing the secretion of anti-inflammatory cytokines, inducible nitric oxide synthase (iNOS)-mediated hampering of IFN-γ production, or forcing arginine shortage. While the immunosuppressive characteristic of MDSCs may help to preserve the tissue homeostasis and prevent hyperinflammation at early stages of the infection, hampering of efficient immune responses proved to exert significant pathogenic effects on severe forms of COVID-19, suggesting the targeting of MDSCs as a potential intervention to reactivate T-cell immunity and thereby prevent the infection from developing into severe stages of the disease. This review tried to compile evidence on the roles of different subsets of MDSCs during viral respiratory infections, which is far from being totally understood, and introduce the promising potential of MDSCs for developing novel diagnostic and therapeutic approaches, especially against COVID-19 disease.