Mammalian membrane sialic acid is the key receptor for influenza virus. Sialidases, the main type of enzyme that can hydrolyze membrane sialic acids in mammalian cells, have the potential to affect the invasion process of influenza viruses, including H1N1. For the first time, this study focused on the regulation mechanism of sialidase NEU1 expression, and revealed that swine-origin influenza (H1N1) virus infection can promote NEU1 expression through histone H3 acetylation, which is regulated by HDAC2 in host cells. This study not only provides evidence for the regulatory mechanisms of mammalian sialase NEU1 expression, but also provides new insights into the host immune defense response against influenza virus infection.