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The pyroptosis execution protein GSDMD is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain from GSDMD-C-terminal domain. How the caspases recognize GSDMD and its connection with caspase activation are unknown. Here, we show site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing pyroptosis. The p10-form autoprocessed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a β sheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the β sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode. Our study reveals an unprecedented substrate-targeting mechanism for caspases. The hydrophobic interface suggests an additional space for developing inhibitors specific for pyroptotic caspases. • Site-specific autoprocessing of caspase-4/11 allows high-affinity binding to GSDMD • Structures of caspase-4/11-GSDMD complexes reveal a substrate-binding exosite • Cleavage of GSDMD relies on the exosite interaction but not tetrapeptide sequence • The caspase-1-GSDMD complex structure shows the same GSDMD-targeting mechanism Structural information provides insights into how site-specific processing of caspases allows the cleavage of the pore-forming protein gasdermin D to result in pyroptosis. [ABSTRACT FROM AUTHOR]