Disruption of the angiopoietin-Tie axis is a common finding in cerebral malaria (CM) patients. Increased concentrations of angiopoietin-2 (Ang-2) and decreased levels of angiopoietin-1 (Ang-1) correlate with disease severity and have been proposed as biomarkers of CM. Brain pericytes have a key role in promoting vascular quiescence through many pathways, including Ang-1 secretion. Despite evidence of pericyte damage on post-mortem samples of CM patients, their role in the pathogenesis of the disease remains unexplored. To address this question, we engineered a 3D microfluidics-based cerebral microvessel model containing both human primary cerebral microvascular endothelial cells and cerebral vascular pericytes. This model replicated pericyte vessel coverage and ultrastructural endothelial-pericyte interactions present in the in vivo brain microvascular bed. 3D brain microvessels experienced an increase in vascular permeability after exposure to purifiedP. falciparum-iRBC egress products. This was accompanied by minor changes in pericyte ultrastructural morphology detected by serial block-face scanning electron microscopy. Luminex quantification of cytokines secreted by bioengineered microvessels revealed a significant decrease in Ang-1 secretion and increase in the Ang-2/Ang-1 ratio, suggesting thatP. falciparum-iRBC egress products directly disrupt pericyte biology. Furthermore, we show that pre-incubation with recombinant Ang-1 partially protects against microvessel barrier breakdown caused byP. falciparum-iRBC egress products. Our approach highlights a novel role of brain pericytes in CM pathogenesis and indicates that dysregulation in the angiopoietin-Tie axis contributes toP. falciparum-mediated vascular dysfunction.