The article explores the multifaceted roles of mitochondria in innate immunity, highlighting their significance beyond their primary function as energy-producing organelles. Mitochondria retain bacterial motifs that are recognized by innate immune cells to trigger inflammation and participate in antimicrobial defense. The review discusses how mitochondrial physiology, from oxidative phosphorylation (OxPhos) to signaling of nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes, including macrophage polarization, efferocytosis, anti-bactericidal activity, antigen presentation, immune signaling, and cytokine regulation. The strict regulation of these processes is crucial for homeostasis, and disruptions can lead to injury or disease. The article also delves into the role of mitochondrial reactive oxygen species (mtROS) in inflammation and antimicrobial activity, the importance of mitochondrial membrane potential (ΔΨ_m) and calcium (Ca²⁺) signaling, and the signaling functions of mitochondrial nucleic acids and metabolites. The findings underscore the central role of mitochondria in innate immunity and suggest potential therapeutic targets for inflammatory diseases.The article explores the multifaceted roles of mitochondria in innate immunity, highlighting their significance beyond their primary function as energy-producing organelles. Mitochondria retain bacterial motifs that are recognized by innate immune cells to trigger inflammation and participate in antimicrobial defense. The review discusses how mitochondrial physiology, from oxidative phosphorylation (OxPhos) to signaling of nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes, including macrophage polarization, efferocytosis, anti-bactericidal activity, antigen presentation, immune signaling, and cytokine regulation. The strict regulation of these processes is crucial for homeostasis, and disruptions can lead to injury or disease. The article also delves into the role of mitochondrial reactive oxygen species (mtROS) in inflammation and antimicrobial activity, the importance of mitochondrial membrane potential (ΔΨ_m) and calcium (Ca²⁺) signaling, and the signaling functions of mitochondrial nucleic acids and metabolites. The findings underscore the central role of mitochondria in innate immunity and suggest potential therapeutic targets for inflammatory diseases.