The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has exposed striking interindividual and interpopulation differences in disease susceptibility, severity, and outcomes. While demographic factors and preexisting comorbidities explain part of this variability, it has become increasingly evident that genetic determinants play a crucial role in shaping host responses to SARS-CoV-2 infection. Among the genetic factors under investigation, mitochondrial DNA (mtDNA) variations have emerged as significant contributors to the complex landscape of COVID-19 pathogenesis and severity. Mitochondria are vital for energy metabolism, immune responses, and antiviral signaling. Consequently, mitochondrial dysfunction or genetic variations can influence viral replication, immune responses, and inflammation, potentially altering disease outcomes. Among 13 protein-coding mitochondrial genes, MT-CYB and MT-ATP6 encode essential proteins for the electron transport chain and ATP synthesis. Thus, polymorphisms in these genes can disrupt mitochondrial function. This chapter aims to elucidate the emerging links between polymorphisms in these two key mitochondrial genes and COVID-19 severity. It will explore the biological functions of these mitochondrial genes, discuss how their variants may influence mitochondrial physiology and immune mechanisms, and summarize current evidence and omics-based approaches connecting these polymorphisms to COVID-19 outcomes within the broader context of health-omics.