Significance Middle East respiratory syndrome coronavirus (MERS-CoV) causes highly lethal respiratory disease. MERS-CoV encodes innate immune antagonists, including accessory proteins NS4a and NS4b, unique to the merbeco lineage of betacoronaviruses, and the nsp15 protein endoribonuclease (EndoU), conserved among all coronaviruses. While mutation of each antagonist protein alone has little effect on innate immunity, infections with recombinant MERS-CoVs with mutations of EndoU in combination with either NS4a or NS4b activate innate signaling pathways and are attenuated for replication. Our data indicate that EndoU and accessory proteins NS4a and NS4b together suppress innate immunity during MERS-CoV infection, to optimize viral replication. This is in contrast to SARS-CoV-2 which activates these pathways and is thus more vulnerable to host innate immune responses.