Infective endocarditis (IE) is a severe cardiovascular disease characterized by the formation of vegetations on heart valves. Our previous research found that streptococcal endocarditis is more common in elderly people and is prone to embolic complications leading to adverse clinical outcomes. von Willebrand Factor (VWF) is a crucial regulatory factor in the formation process and composition of vegetation in bacterial endocarditis, but its mechanism remains to be elucidated. This study investigated the role of VWF in the pathogenesis of Streptococcus mutans-induced endocarditis using two distinct mouse models: damage-induced and inflammation-induced endocarditis. We employed histological analysis, immunofluorescence, scanning electron microscopy, and molecular techniques to elucidate the mechanisms of vegetation formation and the contribution of VWF in each model.Our findings reveal significant differences in the timing and extent of VWF involvement between the two models, with a more rapid and pronounced role in the damage-induced model. VWF knockout mice showed reduced vegetation formation, particularly in the damage-induced model, while VWF supplementation restored vegetation development.These results highlight the critical role of VWF in endocarditis pathogenesis and suggest potential therapeutic strategies targeting VWF for the prevention and treatment of IE. Furthermore, our study provides novel insights into the interplay between VWF and inflammatory responses during endocarditis progression, opening new avenues for understanding the complex pathophysiology of this life-threatening condition.