SARS-CoV-2 rewires host metabolism, optimizing virus production. While glycolysis is necessary, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. Mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides and mitochondrial tRNAs and rRNAs for their translation, and certain mtDNA variants have been linked to increased risk of severe COVID-19, hospitalization, and death. We explored the effects of OXPHOS inhibition on SARS-CoV-2 virus production, and the role of host mtDNA variation on viral replication and pathogenesis. We discovered 5 to 100-fold greater SARS-CoV-2 virus production in infected human ACE2-expressing A549 lung cells with OXPHOS inhibited by mtDNA depletion (ρ⁰ cells), chloramphenicol (CAP)-blocked mitochondrial translation, or chemical inhibition of OXPHOS complexes I, III, and V. OXPHOS inhibition resulted in increased size and distribution of viral replication centers and promoted infectious particle production two hours earlier than parent A549-ACE2 (WT) cells. Subsequently, we found increased glycolytic capacity was required for enhanced viral replication while differences in mitochondrial inflammation were not. Reintroduction of mtDNA from three well-defined maternal lineages into ρ⁰ cells reinstated OXPHOS, impaired SARS-CoV-2 replication, and reversed associated viral and glycolytic correlates below that of WT cells. We identified the mitochondrial unfolded protein response as the likely mitochondrial stress signal driving proviral metabolic rewiring. Additionally, different mtDNA lineages in A549-ACE2 cells showed mild variation in bioenergetic transcriptomes and SARS-CoV-2 replicative capacity. Across two murine models of SARS-CoV-2 pathogenesis, four different viral strains, and three host mtDNA variants, mtDNA background influenced survival and clinical disease progression, with proinflammatory immune protection correlates. In summary, OXPHOS function, both extreme and physiologic variation, can influence SARS-CoV-2 replication and pathogenesis. OXPHOS exerts an antiviral effect through limiting glycolysis in infected cells or via immunometabolic regulation of key immune players. The specific relationship (including directionality) between mtDNA background and COVID-19 severity and sequelae likely depends on a balance of factors influencing the outcome of the host-pathogen interaction, including viral replication and immune response, both influenced by mtDNA variation. Our findings have the potential to mitigate the morbidity and mortality of the ongoing COVID-19 pandemic through mitochondrial-informed therapies and biomarker studies.