SignificanceStreptococcus equisubsp.zooepidemicus(SEZ) are Group C streptococci that cause meningitis in animals and humans. Here, we show SEZ releases membrane vesicles (MVs) that contain the SEZ M protein, SzM. MV provides an efficient means of delivery of SzM to host cells. Endocytosis of these vesicles results in autophagic cell death in hBMECs (human brain endothelial microvascular cells) and disruption of the BBB (blood–brain barrier) in mice. Blockade of MV endocytosis or inactivation of autophagic death attenuated SEZ pathogenicity in mice. Together, these findings provide therapeutic targets for treatment of SEZ infection and extend our knowledge of streptococcal virulence mechanisms.