H2N2 influenza virus, the causative agent of the 1957 "Asian flu" pandemic, has disappeared from circulation. However, H2-influenza viruses are still circulating in avian reservoirs. Combined with the waning of H2N2-specific immunity in the human population, there is a risk of reintroduction of H2N2 influenza virus. Vaccines could help in preventing a future pandemic, but to assess their efficacy animal models are required. We therefore set out to expand the ferret model for H2N2 influenza disease by infecting ferrets intranasally or intratracheally with four different H2N2 viruses to investigate their influence on the severity of disease. The H2N2 viruses were collected either during the pandemic or near the end of H2N2 circulation and covered both clade I and clade II viruses. Infection of ferrets with the different viruses showed that viral replication, disease, and pathology differed markedly between virus isolates and infection routes. Intranasal inoculation induced a severe to mild rhinitis, depending on the virus isolate, and did not lead to lung infection or pathology. When administered intratracheally, isolates that successfully replicated in the lower respiratory tract (LRT) induced a nonlethal disease that resembles that of a moderate pneumonia in humans. Differences in viral replication and disease between viruses could be associated with their binding preference for α2,3- and α2,6-sialic acid. The model presented here could facilitate the development of a new generation of H2N2 influenza vaccines. IMPORTANCE In 1957 the world was subjected to a pandemic caused by an influenza A virus of the subtype H2N2. Although the virus disappeared in 1968, H2 viruses continue to circulate in avian reservoirs. It is therefore possible that the H2N2 influenza virus will be reintroduced into the human population, which can lead to another pandemic. The impact of a new H2N2 influenza pandemic can be mitigated by vaccination. However, these vaccines first need to be developed and tested in animal models. In preparation for this, we expanded the ferret model to mimic the different facets of human H2N2 influenza infection and disease. This model can be used for the development and evaluation of new H2N2 influenza vaccines.