Acute kidney injury (AKI) consistently ranks as one of the leading causes of adverse outcomes among hospitalized and critically ill patients, regardless of advances in diagnosis and intensive care. While conventional views of AKI pathogenesis are primarily based on the ischemia-reperfusion model, they cannot fully explain clinical and biological heterogeneity of the condition. This review considers AKI a multisystem pathological process resulting from microcirculatory dysfunction, endothelial glycocalyx degradation, mitochondrial energy deficiency, immunoinflammatory mechanisms, and regulated cell death. The combination of these factors forms an interconnected pathogenetic network. Emerging evidence supports the systemic nature of this syndrome, driven by coordinated disturbances of the vascular compartment, cellular metabolism, and innate immune responses. Impaired microcirculation and glycocalyx degradation can lead to tissue hypoxia and inflammatory activation, even when macrovascular hemodynamics remain intact. Mitochondrial dysfunction in tubular epithelial cells results in energetic collapse, enhanced oxidative stress, and the release of damage-associated molecular patterns (DAMPs), thereby activating innate immunity. Regulated forms of cell death, including ferroptosis, necroptosis, and pyroptosis, play central roles in AKI pathogenesis, determining the extent of tissue injury, the magnitude of inflammation, and the likelihood of functional recovery. Together, these mechanisms clarify the phenotypic variability of AKI and the limited efficacy of therapeutic strategies focused solely on hemodynamic optimization. Viewing AKI as a multisystem process provides a rationale for the development of pathogenetically targeted and personalized therapeutic approaches.