RNA virus double-stranded RNAs (dsRNAs) are key pathogen-associated molecular patterns. Their sensing by MDA5 and/or RIG-I triggers transient, antivirally protective interferon-stimulated gene (ISGs) expression. We transgenically expressed the RNA-dependent RNA polymerase (RdRp) of the picornavirus Theiler virus at low levels (mRNA FPKM values ~ 2) in mice and found that RdRp templating on host RNAs generated dsRNAs in mouse tissues. The outcome was remarkable, lifelong, body-wide MDA5-MAVS pathway activation and global ISG upregulation at very high levels. MDA5 knockout abrogated this while RIG-I knockout had no effect. The constitutive MDA5 pathway activation conferred robust protection from RNA and DNA viral diseases (EMVC, pseudorabies virus, vesicular stomatitis virus, Friend retrovirus, Theiler virus itself), but in contrast to other chronic MDA5 hyperactivation states, the mice suffer no autoimmune or other health consequences. They further confound expectations by resisting a strong autoimmunity provocation (BM12 model lupus induction). However, when we knocked out one allele of the RNA editor ADAR1, the autoinflammation-protected state of RdRp^tg mice was broken. The result was a severe disease that resembles interferonopathies caused by MDA5 gain-of-function protein mutations. Adar^+/- mice were healthy but Adar^+/- RdRp^tg mice had shortened lifespan, stunted growth, premature fur graying, poorly developed teeth, skeletal abnormalities, and extreme ISG elevations. These features are similar to human Singleton–Merten syndrome, while differing in some respects such as lack of aortic calcification. A-to-I edits were both abnormally distributed and increased (numbers of genes and sites). These results, with a nucleic acid-triggered and MDA5-wild type model, illuminate the ADAR1-MDA5 axis in the healthy regulation of innate immunity and establish that viral polymerase-sourced dsRNA can drive autoinflammatory disease pathogenesis.