Red blood cells (RBCs) are known to function as a refuge for providing food resources and as a shelter against the host's immune system after malaria parasite (Plasmodium) infection. Recent studies have reported significant production of extracellular vesicles (microparticles, MPs) in the circulation of malaria patients. However, it is unclear how these extracellular vesicles are generated and what their biological functions are. In this study, we isolated the MPs from a culture medium of normal RBCs and malaria parasite-infected RBCs (iRBCs), compared their quantity and origins, and profiled their miRNAs by deep sequencing. We found a much larger number of MPs released in the culture of iRBCs than in the culture of normal RBCs. Further investigation indicated that, in these MPs, human argonaute 2 (hAgo2) was found to bind to hundreds of miRNAs. These hAgo2-miRNA complexes were transferred into the parasites, and the expression of an essential malaria antigen, PfEMP1, was downregulated by miR-451/140 through its binding to the A and B subgroups of var genes, a family of genes encoding PfEMP1. Our data suggest for the first time that, through the release of MPs, mature RBCs present an innate resistance to malaria infection. These studies also shed new light on the reason why RBCs' genetic mutation occurs mainly in populations living in intensive malaria endemic areas and on the possibility of using miRNAs as novel medicines for malaria patients.