A central tenet of innate immunology is that potential threats to organismal homeostasis trigger inflammatory programs to eliminate the threat, after which inflammation is silenced to restore homeostasis and normal tissue functions. We understand how inflammatory programs are silenced for many innate immune pathways (e.g. toll-like receptors, common signalling modules such as those activating NF-kB). Here, switching off inflammatory programs in vivo generally involves transcriptional programs that feedback to inhibit regulated gene expression. Inflammasomes are signalling complexes that trigger potent inflammatory responses by regulating proteolysis, rather than transcription. Unlike transcriptional changes, which are inherently reversible, protein cleavage is not reversible. It has remained a major challenge to identify fundamental mechanisms that silence proteolytic signalling cascades and their resultant biological programs. This study provides the first in vivo mechanism for inflammasome signal termination. We generated a knock-in mouse (Casp1.CDL) in which the caspase-1 CARD domain linker (CDL) is mutated to prevent autocleavage-induced protease deactivation, and examined these mice during steady-state and upon major physiological challenges. We discovered that CASP1 CDL autocleavage self-limits inflammasome activity to enforce homeostasis in the steady state, temper inflammatory programs during organ challenge, and reinstate tissue homeostasis following the removal of a major challenge to organ function. The critical importance of CASP1 silencing for homeostasis and restoring tissue function highlights CASP1 as an emerging target for new anti-inflammatory drugs.