The endothelial glycocalyx is a dynamic brush-like layer composed of proteoglycans and glycosaminoglycans, including heparan sulfate (HS) and hyaluronic acid (HA), and is an important regulator of vascular homeostasis. Its structure (thickness ranges from 20 to 6450 nm in different species) not only provides a charge-selective barrier but also serves to anchor mechanosensors such as the glypican-1 (GPC-1)/caveolin-1 (CAV-1) complex and buffers shear stress. In severe acute pancreatitis (SAP), inflammatory factors promote the expression of matrix metalloproteinases (MMPs) and heparinases, which degrade syndecan-1 (SDC-1) and HS, while oxidative stress disrupts HA-CD44 binding, leading to increased capillary leakage and neutrophil adhesion. This degradation process occurs before the onset of multiple organ dysfunction syndrome (MODS), highlighting the potential of the glycocalyx as an early biomarker. More importantly, the regeneration of glycocalyx through endothelial cell synthesis of glycosaminoglycans (GAGs) and shear stress-driven SDC recycling provides therapeutic prospects. This review redefines the pathophysiology of severe acute pancreatitis-associated multiple organ dysfunction (SAP-MODS) by exploring the glycocalyx's central mechanistic role and proposes stabilizing glycocalyx structure as a potential strategy to prevent microcirculatory failure.