Cardiac arrest is a major cause of mortality worldwide, with survival often complicated by the development of post-cardiac arrest syndrome (PCAS). This syndrome results from a complex interplay of ischemia-reperfusion injury, systemic inflammation, and multi-organ dysfunction. Inflammation plays a central role in shaping post-resuscitation outcomes, as the sudden restoration of circulation triggers a cascade of immune responses that can exacerbate tissue damage rather than promote healing. This chapter provides an in-depth exploration of the mechanisms underlying PCAS, detailing the activation of immune pathways, the release of cytokines and oxidative species, and the subsequent endothelial and microvascular dysfunction. It then delves into analyzing the effects of these processes on the main organs involved in PCAS and subsequent multi-organ failure (MOF). The brain, being highly sensitive to oxygen deprivation, is particularly vulnerable, suffering from excitotoxicity, neuronal apoptosis, and blood-brain barrier disruption. The heart, despite being the primary organ resuscitated, experiences myocardial stunning and inflammation-driven fibrosis. Additionally, the lungs and gastrointestinal system, due to their unique roles in immune modulation, become key sites of neutrophil sequestration, oxidative injury, and secondary infections. A deep understanding of these pathophysiological mechanisms is crucial to explain and motivate the clinical manifestations of these phenomena, and a clear picture of the causes that lead to PCAS can help to identify new possible therapeutic targets and strategies (such as counteracting post-cardiac arrest inflammation, including the potential use of immune-modulating agents, neuroprotective interventions, and targeted metabolic therapies), thus improving post-arrest management and ultimately enhancing patient survival and neurological recovery.