ABSTRACT Efferocytosis is the fundamental mechanism by which phagocytes clear apoptotic cells to maintain tissue homeostasis. This process is also closely linked to immune tolerance, metabolic reprogramming, inflammation resolution, and tissue repair. In recent years, research spanning cardiovascular disease, autoimmune disorders, metabolic inflammation, neurodegeneration, and cancer has revealed diverse context‐dependent regulatory networks, including “eat‐me” and “don't‐eat‐me” signals, phagocytic receptors, intracellular signaling pathways, and metabolic checkpoints. Disruption of these regulatory layers contributes to the defective resolution of inflammation, persistent immune activation, and impaired tissue regeneration. However, a unified comparative framework that integrates these mechanisms across different disease states is lacking. In this review, we provide a comprehensive overview of the biology of efferocytosis, from apoptotic cell recognition and engulfment to downstream immunometabolic rewiring. We highlight disease‐specific alterations in atherosclerosis, myocardial infarction, autoimmune diseases, neuroinflammation, and the tumor microenvironment. In addition, we summarize the emerging therapeutic strategies, including receptor agonists, metabolic interventions, engineered extracellular vesicles, and immune checkpoint modulation. Finally, we propose a “full‐cycle” monitoring strategy that integrates imaging‐based quantification, circulating biomarkers, multiomics profiling, and artificial intelligence to enable dynamic assessment of efferocytosis in vivo.