Inflammasomes play important roles in controlling microbial infections and inflammatory disorders. They are signaling platforms assembled from multiple proteins that minimally include the apoptosis-associated speck like protein containing a CARD (ASC) and different NOD-like receptor (NLR) proteins. The NLRs respond to exogenous microbial products and endogenous stress-induced molecules, and assemble the inflammasomes. This results in the activation of caspase-1 (CASP1) and induction of pyroptosis and the subsequent processing of the pro-inflammatory cytokines, Interleukin (IL) -1β and IL-18. The protein kinase R (PKR) has been reported to be a component of the inflammasomes and to promote inflammation. However, our studies in murine models demonstrated that PKR is protective in a variety of inflammatory diseases and, in contrasting to this previous report, we show that PKR has a suppressive role in inflammasome activation. Here we present these findings and delineate the mechanism of how PKR represses inflammasome activity. Briefly, we have found PKR regulates the NLRP3 inflammasome, with distinct dependence for separate NLRP3 activators. This demonstrates an alternate mechanism of action from that previously proposed. Nevertheless, these effects all depend on potassium efflux. Moreover, we test the requirement for PKR kinase activity for this activity. These findings provide critical information to correctly develop therapeutic strategies to combat inflammatory disorders.