The H4 subtype of avian influenza virus (AIV) exhibits a wide host range and is commonly found in migratory waterfowl. Recent studies have revealed that the H4N6 AIV can infect guinea pigs via aerosol transmission without prior adaptation. Additionally, the Q226L/G228S substitutions in the receptor-binding site have led to structural changes in globular head of H4 AIV, resulting in a configuration similar to that of pandemic H2N2 and H3N2 human influenza viruses. This article provides an updated review of the historical evolution, global distribution, adaptive mutations, receptor-binding preferences, and host range of H4 AIV. The insights presented herein will help in assessing the potential risk of future H4 AIV epidemics.