Multi-organ failure contributes to mortality in bacterial sepsis. While pore-forming bacterial toxins are well-known to contribute to lethal infection, the molecular mechanism by which these virulence factors initiate diverse organ injury that progresses to fatal disease remains poorly defined. We demonstrate that during lethal sepsis, Staphylococcus aureus alpha-toxin simultaneously alters platelet activation and promotes neutrophil inflammatory signaling through interaction with its cellular receptor ADAM10. Platelet intoxication prevents endothelial barrier repair, and facilitates formation of injurious platelet-neutrophil aggregates, contributing to lung and liver injury that is mitigated by ADAM10 deletion on platelets and myeloid lineage cells. While platelet or myeloid-specific ADAM10 knockout does not alter sepsis mortality, double knockout animals are highly protected. These results define a pathway by which a single pore-forming toxin utilizes a widely-expressed cellular receptor to coordinate progressive, multi-organ disease in lethal sepsis. As an expression-enhancing ADAM10 polymorphism confers susceptibility to severe human sepsis, our studies highlight a rare molecular focus for investigation of the host-pathogen interaction in human disease.