NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2 −/− and Ripk2 −/− mice are hypersusceptible to influenza A virus infection. Ripk2 −/− cells displayed defective mitophagy leading to enhanced mitochondrial superoxide production and accumulation of damaged mitochondria resulting in increased NLRP3 inflammasome activation and IL-18 production. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1 −/− cells displayed enhanced mitochondrial superoxide production and caspase-1 activation. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating NLRP3 inflammasome activation and IL-18 production via ULK1-dependent mitophagy.