COVID-19 was the most significant infectious-agent-related cause of death in the 2020-2021 period. On average, over 60% of those admitted to ICU facilities with this disease died across the globe. In severe cases, COVID-19 leads to respiratory and systemic compromise, including pneumonia-like symptoms, acute respiratory distress syndrome, and multiorgan failure. While the upper respiratory tract and lungs are the principal sites of infection and injury, most studies on the metabolic signatures in COVID-19 patients have been carried out on serum and plasma samples. In this report we attempt to characterize the metabolome of lung parenchyma extracts from fatal COVID-19 cases and compare them with that from other respiratory diseases. Our findings indicate that the metabolomic profiles from fatal COVID-19 and non-COVID-19 cases are markedly different, with the former being the result of increased lactate and amino acid metabolism, altered energy pathways, oxidative stress, and inflammatory response. Overall, these findings provide additional insights into the pathophysiology of COVID-19 that could lead to the development of targeted therapies for the treatment of severe cases of the disease, and further highlight the potential of metabolomic approaches in COVID-19 research.