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Severe COVID-19 is a major cause of morbidity and mortality worldwide, especially among those with co-morbidities, the elderly, and the immunocompromised. However, the molecular determinants critical for severe COVID-19 progression remain to be fully elucidated. Meta-analyses of transcriptomic RNAseq and single-cell sequencing datasets comparing severe and mild COVID-19 patients have demonstrated that the early expansion of myeloid-derived suppressor cells (MDSCs) could be a key feature of severe COVID-19 progression. Besides serving as potential early prognostic biomarkers for severe COVID-19 progression, several studies have also indicated the functional roles of MDSCs in severe COVID-19 pathogenesis and possibly even long COVID. Given the potential links between MDSCs and severe COVID-19, we examine the existing literature summarizing the characteristics of MDSCs, provide evidence of MDSCs in facilitating severe COVID-19 pathogenesis, and discuss the potential therapeutic avenues that can be explored to reduce the risk and burden of severe COVID-19. We also provide a web app where users can visualize the temporal changes in specific genes or MDSC-related gene sets during severe COVID-19 progression and disease resolution, based on our previous study.