<p>PANoptosis is an emerging regulated cell death that integrates the molecular machinery of apoptosis, necroptosis, and pyroptosis into a combined, highly coordinated process. Defined as a distinct, integrative form of cell death, PANoptosis simultaneously engages these three pathways through a multiprotein scaffold known as the PANoptosome, ensuring robust elimination of infected, damaged, or transformed cells. Initially described in response to viral infections, PANoptosis is now recognized as a critical regulator of immune defense, inflammation, and tissue homeostasis, with broad implications for infectious diseases, cancer, autoimmune disorders, neurodegeneration, and ischemia–reperfusion injury. This review provides a comprehensive overview of the molecular composition of the PANoptosome, key triggers of PANoptosis, and its morphological and biochemical hallmarks. We further discuss its dual roles as both a protective and pathogenic mechanism, highlighting context-dependent contributions to host defense and disease progression. Finally, we examine therapeutic opportunities, including small-molecule inhibitors and gene-editing approaches, and outline current challenges, such as the identification of reliable biomarkers and the need for precision-targeted strategies. By integrating recent advances, this review highlights PANoptosis as a conceptual shift in cell death biology and a promising avenue for novel interventions in inflammation-driven diseases.</p>