Zoonotic infections with emerging influenza viruses occur in the context of population-wide immunity to seasonal strains. Because of the worldwide spread of highly pathogenic clade 2.3.4.4b H5N1 influenza viruses in wild birds, there have been numerous spillover events into mammals. This includes a recent spillover into dairy cows that started an ongoing outbreak across the United States. Human infections with avian and bovine origin H5N1 influenza viruses have been documented, raising concern that these viruses may cause a pandemic. Therefore, using a ferret model, we evaluated the impact of preexisting, infection-elicited immunity on susceptibility to H5N1 infection and on severity of disease. Preexisting immunity to the 2009 pandemic H1N1 influenza virus prevented severe H5N1 disease and reduced susceptibility to infection through direct contact with an infected donor ferret. These studies demonstrate that preexisting immunity to influenza viruses, especially the 2009 pandemic H1N1 virus, is a barrier to infection and disease caused by clade 2.3.4.4b H5N1 viruses.