Inflammasome inhibitors offer tremendous promise as new disease-modifying therapeutics. While inflammasomes mediate host defence against a variety of microbes, they also induce pathological inflammation in human diseases. Inhibitors of one inflammasome (e.g NLRP3 inflammasome) are now entering Phase 2 clinical trials while broader-spectrum inhibitors that block multiple inflammasomes (pan-inflammasome inhibitors) are currently under development for clinical use in diseases that involve pathological signalling by multiple inflammasomes. But such beneficial functions of these new therapeutics might come at as a “trade-off”, as inflammasome signalling also prevents infections. We used a suite of genetic and pharmacological approaches to modulate the activity of a single inflammasome (NLRP3) versus multiple inflammasomes (e.g by targeting caspase-1). We confirmed recent reports that blocking NLRP3 using MCC950 ameliorates the progression of chronic liver disease. We used a genetic approach (Caspase-1 genetic inactivation versus Nlrp3 knockout) to mimic the actions of pan- versus NLRP3-specific inflammasome inhibition. We discovered that, pan-inflammasome inhibition is likely to confer greater disease protection than NLRP3-specific inhibition. Inactivating one or many inflammasomes in disease is, however, likely to have the unwanted therapeutic trade-offs by increasing susceptible to infections, such as Salmonella typhimurium. Together, our research findings address the important question of whether inflammasome-modulating drugs have therapeutic trade-offs that are likely to impact on their clinical use.