Simple SummaryThe costs worldwide of the coronavirus disease 2019 (COVID-19) have been tremendous. With millions of deaths in different countries, understanding biomarkers is essential to diminish the disease burden. For this purpose, a reflective understanding of the pathobiology of COVID-19 is required. During viral infection, some proteins require proteolytic activation and are involved in cell repair and maladaptive organ remodeling. This review summarizes the current findings on the role of increasing matrix metalloproteinases (MMPs) during acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. COVID-19 patients present distinct complications that can be distinguished by MMP levels. MMPs in excess can generate tissue damage and aggravate the possible complications of COVID-19. MMPs participate in chronic inflammation, and their abnormal regulation is associated with human diseases. Interestingly, individuals with comorbidities or pathological conditions are more susceptible to increasing MMPs and to developing severe COVID-19 illnesses. Furthermore, MMP levels can predict the risk of in-hospital death by COVID-19, suggesting possible prognostic roles. Extensive knowledge of MMPs could provide novel perspectives on the symptoms, pathogenesis, and treatment of COVID-19.AbstractMMPs are enzymes involved in SARS-CoV-2 pathogenesis. Notably, the proteolytic activation of MMPs can occur through angiotensin II, immune cells, cytokines, and pro-oxidant agents. However, comprehensive information regarding the impact of MMPs in the different physiological systems with disease progression is not fully understood. In the current study, we review the recent biological advances in understanding the function of MMPs and examine time-course changes in MMPs during COVID-19. In addition, we explore the interplay between pre-existing comorbidities, disease severity, and MMPs. The reviewed studies showed increases in different MMP classes in the cerebrospinal fluid, lung, myocardium, peripheral blood cells, serum, and plasma in patients with COVID-19 compared to non-infected individuals. Individuals with arthritis, obesity, diabetes, hypertension, autoimmune diseases, and cancer had higher MMP levels when infected. Furthermore, this up-regulation may be associated with disease severity and the hospitalization period. Clarifying the molecular pathways and specific mechanisms that mediate MMP activity is important in developing optimized interventions to improve health and clinical outcomes during COVID-19. Furthermore, better knowledge of MMPs will likely provide possible pharmacological and non-pharmacological interventions. This relevant topic might add new concepts and implications for public health in the near future.