Thrombocytopenia is a critical factor to predict the onset of dengue hemorrhagic fever. CLEC5A (also known as MDL-1) and CLEC2 are Syk-coupled myeloid C-type lectins receptors (Syk-CLRs) expressed in macrophages/neutrophils and platelets, respectively. We have shown that dengue virus (DV) activates NALP3 inflammasome and induces proinflammatory cytokines from macrophages via CLEC5A, and blockade of CLEC5A is able to attenuate DV-induced hemorrhaging shock and lethality. In this study, we further found that DV activate platelets via CLEC2, and DV-activated platelet-derived microparticles (DV-PMPs) induced ‘neutrophil extracellular trap’ (NET) formation and proinflammatory cytokine release via co-stimulation of CLEC5A and TLR2. Furthermore, co-incubation of DV with neutrophils and platelets simultaneously not only resulted reduced platelet counts, but also enhanced vascular permeability change in vitro. Furthermore, blockade of both CLEC5A and TLR2 not only attenuated thrombocytopenia, but also protect mice from DV-induced lethality in vivo. Thus, CLEC2-activated PMP plays a critical role in DV-induced NET formation and proinflammatory cytokine production, and blockade of CLEC5A and TLR2 simultaneously is a promising approach to prevent DV-induced thrombocytopenia and lethality in the future.