Mitochondrial DNA (mtDNA) variation has traditionally been investigated in the context of human evolution and rare mitochondrial diseases; however, growing evidence suggests that it may also contribute to susceptibility to common metabolic disorders. This review integrates current knowledge of mitochondrial biology, mtDNA genetics, heteroplasmy, and the global distribution of mitochondrial haplogroups to examine their roles in health and disease. In this narrative review, we synthesized English-language studies identified through PubMed, Scopus, and Web of Science from January 1988 to May 2026, prioritizing evidence according to relevance, scientific contribution, recency, and historical significance. We summarize evidence showing how pathogenic variants (PVs) in mtDNA genes impair oxidative phosphorylation (OXPHOS), increase reactive oxygen species (ROS) production, and disrupt cellular bioenergetics, thereby contributing to the multisystem manifestations of mitochondrial diseases. We further discuss population-specific mitochondrial haplogroups and their reported population-specific associations with metabolic phenotypes, including obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD). Finally, we review recent advances in next-generation sequencing technologies and their contributions to the molecular diagnosis of mitochondrial diseases and the characterization of genotype–phenotype relationships. Collectively, current evidence supports a well-established pathogenic role for specific mtDNA variants in primary mitochondrial disorders, whereas the contributions of common polymorphisms and haplogroups to complex metabolic disease remain largely associative and require further replication and functional validation.