An effective, tightly regulated immune response is critical for patients to recover from viral infections like COVID-19. Understanding immune regulation can allow researchers to develop better therapeutics and management techniques for patients. One class of factors involved with immune regulation are soluble immune mediators, which play roles in the dynamic interactions between ligands and membrane-bound receptors. Normally, soluble immune mediators help maintain and restore health after pathological events, but sometimes their dysregulation causes pathology instead. SARS-CoV-2 infection impacts many of these soluble immune mediators and, through them, many physiological processes. Thus, dysregulated shifts in the concentration of some of these molecules could be playing a significant role in COVID-19 severity and mortality. Therefore, modulating circulating levels of some mediators may have potential as a therapeutic option for COVID-19 patients, but more research is needed to understand the specific mechanisms of action linking soluble immune mediators, immune regulation, and COVID-19.