The high mortality of coronavirus disease 2019 (COVID-19) patients is due to their progression to cytokine-associated organ injuries, primarily the acute respiratory distress syndrome (ARDS). The uncertainties in the molecular mechanisms leading to the switch from the early virus infection to the advanced stage ARDS is a major gridlock in therapeutic development to reduce mortality. Previous studies in our laboratory have identified matrix metalloprotease-3 (MMP3) as an important mediator of bacterial lipopolysaccharide (LPS)-induced ARDS, particularly in the exudative phase. Our studies have also reported elevated plasma MMP3 activity levels in the ARDS patients and that inhibition of MMP3 can reduce the severity of LPS-induced ARDS in mice. Given these observations, targeting MMP3 could be a potential option to treat COVID-19 patients with ARDS, and measurement of MMP3 activity in the plasma may serve as a biomarker for the early detection of ARDS in COVID-19 patients.