Immune and metabolic processes are increasingly recognized as interconnected determinants of disease progression. Immunometabolic reprogramming describes the dynamic adaptation of cellular energy metabolism and immune function to environmental and pathological stress, with persistent dysregulation contributing to chronic inflammation, metabolic dysfunction, and tissue injury. This review develops a systems-level framework for understanding how energy sensing, inflammatory signaling, mitochondrial function, and organ-specific metabolic states interact to shape disease phenotypes. We examine the central role of the AMPK–mTOR axis, metabolic switching between oxidative phosphorylation and glycolysis, and inflammatory pathways involving NF-κB and cytokine networks in coordinating immune–metabolic responses. Particular emphasis is placed on mitochondria as an integration hub linking bioenergetic status, redox signaling, and inflammatory activation. Organ-specific manifestations across the liver, adipose tissue, brain, and cardiovascular system are discussed to illustrate how shared immunometabolic principles generate distinct tissue phenotypes. We further consider evidence from systems biology and multi-omics approaches, highlighting their potential to identify network-level disease signatures, mechanistic subtypes, and therapeutic vulnerabilities. Current therapeutic strategies targeting AMPK, mTOR, inflammatory signaling, oxidative stress, and mitochondrial dysfunction are evaluated, with emphasis on the limitations of single-pathway interventions and the emerging rationale for integrated or combination approaches. Finally, the translational potential of composite immune–metabolic biomarkers, precision immunometabolic stratification, computational modeling, and adaptive therapeutic monitoring is discussed. Collectively, immunometabolic reprogramming provides a unifying framework that connects systemic energy homeostasis with inflammatory signaling and organ dysfunction, offering a mechanistic basis for the development of more precise and durable therapeutic strategies across diverse disease states.