COVID-19 can trigger an intense systemic inflammation and prothrombotic state, leading to a rapid and disproportionate deterioration of lung function. An effective screening tool is essential to identify the patients at risk for severe disease. This observational study was conducted on hospitalized patients with moderate and severe COVID-19 pneumonia in a general hospital in Mexico City between 1 March 2021 and 15 March 2021. Serum samples were analyzed to explore the role of biomarkers of inflammation, coagulation, oxidative stress, and endothelial damage with the severity of the disease. Our results demonstrated that Syndecan-1 and nitrites/nitrates showed a high correlation in severely ill patients. In conclusion, COVID-19 patients with elevated levels of SDC-1 were associated with severe disease. This molecule can potentially be used as a marker for the progression or severity of COVID-19. Preservation of glycocalyx integrity may be a potential treatment for COVID-19.