Cerebral malaria (CM) continues to be associated with major morbidity and mortality, particularly in children aged <5 years in sub-Saharan Africa. Although the biological mechanisms underpinning severe malaria pathophysiology remain incompletely understood, studies have shown that cytoadhesion of malaria-infected erythrocytes to endothelial cells (ECs) within the cerebral microvasculature represents a key step in this process. Furthermore, these studies have also highlighted that marked EC activation, with secretion of Weibel-Palade bodies (WPBs), occurs at a remarkably early stage following malaria infection. As a result, plasma levels of proteins normally stored within WPBs (including high-molecular-weight von Willebrand factor [VWF] multimers, VWF propeptide, and angiopoietin-2) are significantly elevated. In this review, we provide an overview of recent studies that have identified novel roles through which these secreted WPB glycoproteins may directly facilitate malaria pathogenesis through a number of different platelet-dependent and platelet-independent pathways. Collectively, these emerging insights suggest that hemostatic dysfunction, and in particular disruption of the normal VWF-ADAMTS-13 axis, may be of specific importance in triggering cerebral microangiopathy. Defining the molecular mechanisms involved may offer the opportunity to develop novel targeted therapeutic approaches, which are urgently needed as the mortality rate associated with CM remains in the order of 20%.