COVID-19 has claimed millions of lives during the last 3 years since initial cases were reported in Wuhan, China, in 2019. Patients with COVID-19 suffer from severe pneumonia, high fever, acute respiratory distress syndrome (ARDS), and multiple-organ dysfunction, which may also result in fatality in extreme cases. Cytokine storm (CS) is hyperactivation of the immune system, wherein the dysregulated production of proinflammatory cytokines could result in excessive immune cell infiltrations in the pulmonary tissues, resulting in tissue damage. The immune cell infiltration could also occur in other tissues and organs and result in multiple organs' dysfunction. The key cytokines implicated in the onset of disease severity include TNF-α, IFN-γ, IL-6, IL-1β, GM-CSF, and G-CSF. Controlling the CS is critical in treating COVID-19 disease. Therefore, different strategies are employed to mitigate the effects of CS. These include using monoclonal antibodies directed against soluble cytokines or the cytokine receptors, combination therapies, mesenchymal stem cell therapy, therapeutic plasma exchange, and some non-conventional treatment methods to improve patient immunity. The current review describes the role/s of critical cytokines in COVID-19-mediated CS and the respective treatment modalities.