<p>Mitochondria, traditionally recognized for their energy-producing function, also play a vital role in immune responses by regulating host–bacteria interactions. This narrative review examines emerging evidence on how host mitochondrial DNA (mtDNA) influences bacterial infections, emphasizing its active involvement in immune defense and disease progression. We first discuss how mitochondrial dynamics and stress responses support infection control, followed by an exploration of mtDNA as an intrinsic danger signal. The review highlights key immune pathways and inflammatory mechanisms triggered by mtDNA release. When mtDNA escapes into the cytoplasm or extracellular space, these pathways initiate strong antibacterial defenses. Genetic diversity in mtDNA sequences can shape immune responses and determine susceptibility to infection or inflammation. Bacterial infections often induce mtDNA release from host cells, which can either enhance immune activation or aggravate tissue damage. This dual function underscores mtDNA’s complex role,promoting bacterial clearance while sometimes contributing to pathology that aids bacterial persistence. Pathogens have evolved sophisticated strategies to evade mtDNA-mediated immunity by damaging mitochondria, controlling mtDNA release, or altering immune signaling. These host–pathogen interactions highlight the potential of circulating mtDNA as a biomarker for disease prognosis and a target for therapeutic innovation. Integrating advances from immunology, microbiology, and mitochondrial genetics, this review underscores mtDNA’s central role in bacterial infections and its promise for guiding future diagnostic and therapeutic developments.</p>