The lack of innovation in Von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by VWD patients. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant Von Willebrand factor (VWF) concentrates have started to emerge. Here we report an original approach using synthetic platelet (SP) nanoparticles for treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD). SP are liposomal nanoparticles decorated with peptides enabling them to concomitantly bind to collagen, VWF and activated platelets. In vitro, using various microfluidic assays, we show the efficacy of SP to improve thrombus formation in VWF-deficient condition (with human platelets) or using blood from VWD-2B mice and VWF-deficient mice (VWF-KO, i.e., type 3 VWD). In vivo, using a tail clip assay, SP treatment reduced blood loss by 35% in VWD-2B mice and 68% in VWF-KO mice. Additional studies using nanoparticles decorated with various combinations of peptides demonstrated that the collagen binding peptide, although not sufficient by itself, was absolutely crucial for SP efficacy in VWD-2B while all three peptides appeared necessary for VWF-KO mice. Clot imaging by immunofluorescence and scanning electron microscopy revealed that SP treatment of VWF-KO mice led to a strong clot, similar to those obtained in wild-type mice. Altogether, our results show that SP could represent an attractive therapeutic alternative for VWD, especially considering their long half-life and stability.