Enteropathogenic Escherichia coli (EPEC) is a human-restricted, clinically significant diarrhoeagenic pathogen that colonises the gut mucosa of hosts via the formation of characteristic attaching and effacing (A/E) lesions. To establish infection and cause disease, EPEC subverts a range of host cell processes through the injection of a suite of bacterial effector proteins into host cells via a Type 3 Secretion System (T3SS). EPEC virulence is critically reliant on the T3SS-delivered Translocated intimin receptor (Tir), which triggers actin polymerisation at the bacterial attachment site in intestinal epithelial cells. However, the manner in which EPEC effector proteins activate and subvert signalling pathways in human immune cells, such as macrophages, remains to be established. During infection the innate immune compartment of the intestinal mucosa plays a pivotal role in antimicrobial immunity, and activation of inflammasome signalling pathways is central to bacterial clearance. This has been established in vivo using the model A/E pathogen Citrobacter rodentium. Interestingly, although evolutionarily closely related to the enteric pathogens Citrobacter, Salmonella and Shigella, the EPEC T3SS needle and flagellin proteins evade detection by inflammasomes. Currently EPEC-induced inflammasome activation in human macrophages is poorly understood. Here I show that infection of human primary macrophages with EPEC rapidly induces NLRP3-inflammasome-driven pyroptosis in a strictly Tir-dependent manner. Mechanistically, Tir-induced actin polymerisation, either via Tir tyrosine phosphorylation and the Nck-N-WASP-ARP2/3 actin polymerisation pathway, or through Tir and the Nck-mimicking effector TccP, stimulated rapid caspase-4-dependent inflammasome responses. Notably, in contrast to caspase-4-driven pyroptosis induced by non-pathogenic E. coli or cytosolic LPS, both pyroptosis and cytokine processing in response to EPEC infection required NLRP3, ASC and caspase-1, and occurred independently of pannexin-1. This study identifies a surprising and indispensable role for both human caspase-4 and NLRP3 in detecting EPEC, and an essential role for pathological actin polymerisation by a bacterial effector in inflammasome activation.