Acute Respiratory Distress Syndrome is characterized by the accumulation of inflammatory fluid in the lung alveoli and is the main factor responsible for the high mortality in patients with COVID-19. In addition to the obvious pathogenic function of SARS-CoV-2 viral RNA, surface proteins, in particular, the Spike protein, which binds to the human angiotensin-converting enzyme 2 and is primed by the host serine protease TMPRSS2, play an important role in the development of the ARDS. The clinical worsening in the later phases of COVID-19 is thought to result from Spike protein binding to the pulmonary microvascular endothelium and epithelium, which leads to a damaged respiratory tract and ultimately a systemic inflammatory response or cytokine storm. In this study, we used our SARS-CoV-2 Spike protein Subunit 1-induced K18-hACE2 mouse model to develop an entirely new therapeutic strategy using the reversible, selective, allosteric inhibitor of PTP4A3 phosphatase KVX-053. Our findings suggest that this novel PTP4A3 inhibitor prevents or mitigates the initial pulmonary damage and halts the lethal cytokine storm.