Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation. Display omitted •Inactivation of RhoA by Yersinia effectors YopE and YopT triggers the pyrin inflammasome•Pyrin activation is blocked by YopM, an effector that binds to RSK and PRK kinases•YopM hijacks PRKs, which regulate pyrin by phosphorylation of 14-3-3 binding sites•Inhibition of the pyrin inflammasome by YopM is essential for Yersinia virulence Pathogenic Yersinia secrete effectors called Yops, which can trigger or inhibit protective immune responses. Chung et al. demonstrate that both YopE and YopT inactivate RhoA, resulting in activation of the pyrin inflammasome. Consequently, Yersinia maintain virulence by delivering YopM, which hijacks host kinases to phosphorylate pyrin and inhibit inflammasome activation.