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SARS-CoV-2 evades most innate immune responses, but may still be vulnerable to some. Here, we systematically analyzed the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract antiviral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologues of closely-related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling and infection experiments confirmed potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists, but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches., Graphical Abstract, Hayn et al. analyze the impact of individual SARS-CoV-2 proteins on virus sensing, interferon signaling and autophagy. They define the repertoire of viral antagonists of innate immune defenses, determine selected underlying mechanisms and identify remaining vulnerabilities of SARS-CoV-2.