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Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade IFN responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks IFN signaling independently of its cell death inhibitory activity. Rather, IFN inhibition was mediated by the binding of OspC1 and OspC3 to the Ca2+ sensor calmodulin (CaM), blocking CaM kinase II and downstream JAK/STAT signaling. The growth of Shigella lacking OspC1 and OspC3 was attenuated in epithelial cells and in a murine model of infection. This phenotype was rescued in both models by the depletion of IFN receptors. OspC homologs conserved in additional pathogens not only bound CaM but also inhibited IFN, suggesting a widespread virulence strategy. These findings reveal a conserved but previously undescribed molecular mechanism of IFN inhibition and demonstrate the critical role of Ca2+ and IFN targeting in bacterial pathogenesis. [Display omitted] • Interferons (IFNs) and IFN-stimulated genes (ISGs) restrict Shigella infection • Shigella OspC1 and OspC3 effectors block IFN signaling and ISG expression • OspC effectors bind calmodulin (CaM), inhibiting CaMKII and STAT1 phosphorylation • Δ ospC1/C3 Shigella is attenuated in WT but not in IFN-deficient cells and mice The OspC type-III-secreted effectors in Shigella bind calmodulin and block interferon signaling, independently of the cell-death-inhibitory activities of this family of proteins. Conservation of this function in homologs of other bacterial species suggests a common role for Ca2+ and interferon targeting in bacterial pathogenesis. [ABSTRACT FROM AUTHOR]