Inflammasomes are signalling hubs that assemble in response to cell stress or microbial infection, and provide an activation platform for the zymogen protease, caspase-1. Upon activation, caspase-1 triggers the maturation and secretion of potent pro-inflammatory mediators (interleukin-1b and -18) and induces cell lysis (pyroptosis), culminating in the activation of the immune system and antimicrobial defence. Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms terminating cellular caspase-1 activity are unknown. In this study, we define the precise molecular events initiating caspase-1 protease activity within the inflammasome, and negative regulatory mechanisms governing the duration of inflammasome signalling in cells. We show that the inflammasome-caspase-1 complex functions as a holoenzyme that directs the location of caspase-1 activity, but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.