Pathogens causing severe septicemia often lead to life-threatening complications such as hemolytic anemia and venous thrombosis, but the underlying mechanisms remain unclear. Here, we investigate how Vibrio vulnificus infection, at sub-hemolytic levels, induces critical alterations in human red blood cells (RBCs). These alterations include morphological transformations to echinocytes and spherocytes, externalization of phosphatidylserine (PS), and generation of microvesicles. These changes collectively enhance RBC procoagulant activity, promoting thrombin generation and RBC aggregation, which are key processes in venous thrombosis. The multifunctional autoprocessing repeats-in-toxin (MARTX) toxin, encoded by the rtxA gene of V. vulnificus, is significantly upregulated upon exposure to RBCs. Genetic deletion of rtxA eliminates these procoagulant effects, highlighting the MARTX toxin\'s essential role. Further analyses reveal that MARTX toxin-mediated pore formation leads to increased intracellular calcium levels, activating caspase-3 and scramblase, and consequently facilitating PS exposure. These findings were validated in vivo using a rat venous thrombosis model, confirming the pivotal role of MARTX toxin in thrombus formation. Our study provides novel insights into pathogen-induced thrombosis and offers potential therapeutic targets for managing infection-associated coagulopathies.