Patients with obesity and/or diabetes have worse outcomes in SARS-CoV-2 infection, and the virus has been shown to promote insulin resistance and β-cell dysfunction in individuals with no previous history of metabolic disease. As such, there is interest in repurposing anti-diabetic drugs for COVID-19. This study reports that blocking the mitochondrial pyruvate carrier (MPC) with the second-generation insulin sensitizer MSDC-0602 K (MSDC) reduces disease in mice infected with SARS-CoV-2, as well as in mice infected with influenza virus. Mice with a myeloid-restricted deletion of MPC also had better outcomes in these viral infections, and MSDC was shown to restrict the inflammatory activity of both mouse and human alveolar macrophages. In virus-infected obese mice, treatment with MSDC reduced hyperglycaemia as well as airway inflammation. Mechanistically, MSDC improved mitochondrial fitness and reduced succinate and acetyl-CoA levels, which destabilized HIF-1α and limited inflammatory responses driven by the HIF-1α pathway.