The molecular basis of the receptor recognition for pectin-derived heteropolysaccharides has remained subtle. Through combining systematic literature mining with computational docking and microsecond-scale molecular dynamics simulations, we showed that the leucine-rich repeat concave surface of Toll-like receptor 4 constitutes the principal carbohydrate-binding domain, with galactan-rich polysaccharide segments proving binding selectivity and structural rigidity within this interface. Orthogonal validation through surface plasmon resonance and secreted embryonic alkaline phosphatase reporter assays revealed that pectic heteropolysaccharides activate Toll-like receptor 4 via an unconventional, MD-2-independent, multivalent engagement mode. Fluorescence colocalization microscopy further established that these polysaccharides selectively nucleate Toll-like receptor 4 clustering at the macrophage plasma membrane during receptor-mediated endocytosis, thereby triggering downstream pro-inflammatory polarization through coordinate activation of ERK, p38 MAPK, and NF-κB pathways. Our data establish a conceptually novel brush-like model of glycan pattern recognition by Toll-like receptor 4, in which diffuse polysaccharide contact progressively condenses into organized receptor assemblies that license inflammatory signaling. This mechanistic framework provides a rational blueprint for engineering polysaccharide-based immunotherapeutic agents with defined receptor-level pharmacology.