Interferonopathies drive autoimmunity but can also impair host responses to pathogens, including viral infections. To better understand viral susceptibility of patients with STAT1 gain-of-function (GOF) mutations, we generated conditional knockin mouse models to elucidate disease mechanisms and relevance of different immune subsets. Virally infected Stat1 GOF mice exhibited impaired early IFN-γ production from innate lymphocytes and lethality because of excess prolonged multicytokine production. The presence of the Stat1 GOF allele resulted in premature usage of interferon-stimulated gene factor 3 (ISGF3) over the normal STAT4-AP-1-dependent transcriptomic program in activated innate lymphocytes. Administration of anti-IFN-γ antibodies in wild-type (WT) mice after infection phenocopied Stat1 GOF mice presenting exaggerated inflammation despite viral control. Conversely, early administration of exogenous IFN-γ to infected Stat1 GOF mice prevented lethality and exaggerated cytokine response. Although Stat1 GOF mutations facilitate IFN-γ-mediated autoimmunity, early IFN-γ responses to viral infection via a normal STAT4 program were impaired, leading to overcompensated inflammatory responses in Stat1 GOF mice.