Significance SARS-CoV-2 emergence in late 2019 led to the COVID-19 pandemic that has had devastating effects on human health and the economy. While early innate immune responses are essential for protection against virus invasion and inadequate responses are associated with severe COVID-19 disease, gaps remain in our knowledge about the interaction of SARS-CoV-2 with host antiviral pathways. We characterized the innate immune response to SARS-CoV-2 in relevant respiratory tract-derived cells and cardiomyocytes and found that SARS-CoV-2 activates two antiviral pathways, oligoadenylate synthetase–ribonuclease L and protein kinase R, while inducing minimal levels of interferon. This is in contrast to Middle East respiratory syndrome-CoV, which inhibits all three pathways. Activation of these pathways may contribute to the distinctive pathogenesis of SARS-CoV-2.