Cell entry of influenza A virus (IAV) was reported to be promoted by epidermal growth factor receptor (EGFR). On the other hand, binding of heparin-binding EGF-like growth factor (HB-EGF) to EGFR leads to internalisation and degradation of the receptors. This study aimed to testify whether or not HB-EGF-induced downregulation of EGFR could attenuate IAV cell entry and subsequently diminish the infection. Immunoblotting and plaque assay revealed that HB-EGF-induced degradation of EGFR led to reduction of viral matrix 1 protein level and suppressed virion production. In addition, immunoblotting and imaging flow cytometric analysis demonstrated that IAV-induced phosphorylation of STAT1 and its localisation to nucleus in the early stage of infection were inhibited by HB-EGF treatment. This suggested the potential of HB-EGF in modulating uncontrolled and exaggerated inflammatory response caused by IAV infection. Together these findings attest the potential of HB-EGF mediated endocytosis and degradation of EGFR as a novel anti-IAV strategy.