The predicted increase in p38/MAPK activity led us to investigate the effects of p38/MAPK inhibition on pro-inflammatory cytokine production and viral replication in SARS-CoV-2-infected cells. Recent immunological studies have indicated that increased IL-6, IL-10, and TNF-α and lymphopenia are associated with severe COVID-19 cases (Pedersen and Ho 2020). The p38/MAPK pathway responds to and controls production of potentially harmful pro-inflammatory cytokines. Several pathogenic viral infections induce a p38/MAPK signaling state that exhibits uncontrolled positive feedback regulation, leading to excessive inflammation associated with severe disease. Inhibition of p38/MAPK signaling suppressed the overproduction of inflammatory cytokines induced by several viral infections, including SARS-CoV, Dengue virus, and influenza A virus, improving survival in mice (Fu et al., 2014; Growcott et al., 2018; Jimenez-Guardeño et al., 2014). However, p38/MAPK inhibition did not directly impair the virus in these cases but, instead, the host’s immune response to the infection. In contrast, during SARS-CoV-2 infection, p38/MAPK inhibition suppressed cytokine production and impaired viral replication by a still unknown mechanism, suggesting that p38/MAPK inhibition may target multiple mechanisms related to COVID-19 pathogenesis.