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Thermostable direct haemolysin (TDH) is the key virulence factor secreted by the human gastroenteric bacterial pathogen Vibrio parahaemolyticus. TDH is a membrane‐damaging pore‐forming toxin. It evokes potent cytotoxicity, the mechanism of which still remains under‐explored. Here, we have elucidated the mechanistic details of cell death response elicited by TDH. Employing Caco‐2 intestinal epithelial cells and THP‐1 monocytic cells, we show that TDH induces some of the hallmark features of apoptosis‐like programmed cell death. TDH triggers caspase‐3 and 7 activations in the THP‐1 cells, while caspase‐7 activation is observed in the Caco‐2 cells. Interestingly, TDH appears to induce caspase‐independent cell death. Higher XIAP level and lower Smac/Diablo level upon TDH intoxication provide plausible explanation for the functional inability of caspases in the THP‐1 cells, in particular. Further exploration reveals that mitochondria play a central role in the TDH‐induced cell death. TDH triggers mitochondrial damage, resulting in the release of AIF and endonuclease G, responsible for the execution of caspase‐independent cell death. Among the other critical mediators of cell death, ROS is found to play an important role in the THP‐1 cells, while PARP‐1 appears to play a critical role in the Caco‐2 cells. Altogether, our work provides critical new insights into the mechanism of cell death induction by TDH, showing a common central theme of non‐classical programmed cell death. Our study also unravels the interplay of crucial molecules in the underlying signalling processes. Our findings add valuable insights into the role of TDH in the context of the host–pathogen interaction processes. [ABSTRACT FROM AUTHOR]