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Thromboinflammation is the pathological hallmark of diverse cardiovascular and inflammatory disorders. Platelets are the key effector cells linking thrombosis and inflammation and are known to express Toll-like receptors (TLRs) including TLR4. High mobility group box 1 protein (HMGB1) initiates a thromboinflammatory cascade by functioning as a primary ligand for platelet TLR4. Despite its central role in thromboinflammatory responses, HMGB1-TLR4 axis remains an unmet clinical need. In this study, we explored therapeutic potential of Low-molecular-weight Fucoidan (LMF) in modulating HMGB1-TLR4-driven thromboinflammation. It was found that LMF interacted with HMGB1 and interrupted HMGB1-dependent TLR4-mediated pro-inflammatory signaling. By targeting HMGB1, LMF profoundly suppressed early TLR4-driven platelet outside-in signaling events, encompassing intracellular calcium mobilization, Akt-upregulation and subsequent αIIbβ3 activation. This early signaling interception was manifested as functional deficit including impaired activation, reduced platelet aggregation and thrombus consolidation under shear conditions. Importantly, LMF disrupted HMGB1-driven platelet-leukocyte crosstalk as evident through reduced formation of neutrophil-extracellular traps. Further, LMF administration conferred cerebrovascular protection in mice by limiting HMGB1-driven thrombus growth, accompanied by marked reduction in cerebral infarction and systemic inflammation as reflected by decreased circulating IL-6 concentration. These findings demonstrate that LMF restrains HMGB1-dependent TLR4-driven thrombosis and vascular inflammation and could be a promising therapeutic intervention for thromboinflammatory disorders.