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Brazil has the second highest COVID-19 death rate while Rio de Janeiro is among the states with the highest rate in the country. Although effective vaccines have been developed, it is anticipated that the ongoing COVID-19 pandemic will transition into an endemic state. Under this scenario, it is worrisome that the underlying molecular mechanisms associated with the disease clinical evolution from mild to severe, as well as the mechanisms leading to long COVID are not yet fully understood. In this study,1H Nuclear Magnetic Resonance spectroscopy and Liquid Chromatography-Mass spectrometry-based metabolomics were used to identify potential pathways and metabolites involved in COVID-19 pathophysiology and disease outcome. We prospectively enrolled 35 severe RT-PCR confirmed COVID-19 cases within 72 hours from intensive care unit admission, between April and July 2020 from two reference centers in Rio de Janeiro, and 12 samples from non-infected control subjects. Of the 35 samples from COVID-19 patients, 18 were from survivors and 17 from non-survivors. We observed that patients with severe COVID-19 had their plasma metabolome significantly changed if compared to control subjects. We observed lower levels of glycerophosphocholine and other choline-related metabolites, serine, glycine, and betaine, indicating a dysregulation in methyl donors and one-carbon metabolism. Importantly, non-survivors had higher levels of creatine/creatinine, 4-hydroxyproline, gluconic acid andN-acetylserine compared to survivors and controls, reflecting uncontrolled inflammation, liver and kidney dysfunction, and insulin resistance in these patients. Lipoprotein dynamics and amino acid metabolism were also altered in severe COVID-19 subjects. Several changes were greater in women, thus patient’s sex should be considered in pandemic surveillance to achieve better disease stratification and improve outcomes. The incidence of severe outcome after hospital discharge is very high in Brazil, thus these metabolic alterations may be used to monitor patients’ organs and tissues and to understand the pathophysiology of long-post COVID-19.