Acute pancreatitis (AP) remains a complex inflammatory disease in which early microcirculatory failure plays a central role in determining severity, organ dysfunction, and clinical outcomes. Despite major advances in understanding its pathobiology, therapeutic strategies targeting microvascular impairment, endothelial injury, and perfusion disturbances remain fragmented and inconsistently translated into practice. This comprehensive narrative review critically synthesizes current evidence on pancreatic microcirculatory dysfunction and its therapeutic implications. We integrate data from contemporary models, including endothelial glycocalyx degradation, capillary leak phenomena, leukocyte–endothelium interactions, mitochondrial dysfunction, and splanchnic hypoperfusion, establishing microcirculatory collapse as a unifying mechanism in the progression to severe AP. Furthermore, the review critically evaluates therapeutic interventions aimed at maintaining or restoring microvascular integrity, including optimized fluid resuscitation, low-molecular-weight heparin, ulinastatin, epidural analgesia, continuous hemofiltration, and experimental endothelial-protective agents. Evidence suggests that early, controlled hydration, anticoagulation in select cases, and epidural strategies may improve perfusion and reduce complications, while emerging therapies targeting glycocalyx preservation, mitochondrial stability, and SIRT1-FOXO1 pathways show promising translational potential. However, heterogeneity among studies, limited high-quality randomized trials, and variations in timing and patient selection highlight persistent gaps. Overall, this review consolidates microcirculatory dysfunction as a central therapeutic target in acute pancreatitis and underscores the need for standardized protocols, high-quality RCTs, and precision-based approaches to modify the early trajectory of severe disease.