Influenza viruses causes acute respiratory infections which may lead to annual seasonal epidemics. In the 20th century, three major pandemics occurred in 1918-1919,1957 and 1968. Influenza infection causes more than 90% of deaths among people over 65 years of age. The CDC recommends the antiviral drugs baloxavir marboxil (Xofluza), oseltamivir (Tamiflu) and zanamivir (Relenza) for both influenza prevention and treatment. Thiocyanate (SCN-) is a natural compound in the human body. SCN- plays an important role in the innate immune system as a precursor of the antimicrobial hypothiocyanous acid (HOSCN). HOSCN is generated from SCN- by peroxidases using H2O2. HOSCN has antimicrobial activities against various viruses and bacteria in vitro. Our group has shown that HOSCN effectively inactivates several respiratory pathogens in vitro and in vivo, including influenza A and B viruses. We hypothesized that in vivo administration of SCN-, the substrate for HOSCN, helps the immune system of the airways to fight influenza infections. Our results revealed that oral administration of 400 μg/kg/day NaSCN between 2–7 days post-infection (dpi) reduced mortality in C57BL/6J mice by more than 90% when infected with one of the following influenza virus strains: A/PR8/1934 (H1N1), A/Hong Kong/1968 (H3N2) or B/Lee/1940 (repeated two times). This beneficial therapeutic effect of oral SCN- was entirely independent of the Duox1 gene as Duox1-deficient animals were rescued by SCN- to the same extent as wild-type mice. SCN- acted in a dose-dependent manner as 100% mortality observed in A/PR8/34-infected animals was entirely prevented by 200 or 400 μg/kg/day NaSCN treatment (2-7 dpi). C57BL/6J mice infected with a lethal dose of B/Florida/04/2006 were also largely rescued from mortality when treated with oral SCN- in the same way. Lung histology performed at 5 dpi demonstrates robust lung disease in A/PR8/34 or B/Florida/04/2006 infected mice that were mainly prevented by oral SCN- treatment (400 μg/kg/day, 2-7 dpi). Influenza lung viral titers were also drastically reduced in SCN-- treated mice at 4 dpi, compared to untreated animals following A/PR8/34 or B/Florida/04/2006 challenges.