Identification of host factors that play a key role in viral replication is of great importance for antiviral development. Metabotropic glutamate receptor subtype 2 (mGluR2) is the receptor to trigger clathrin-mediated endocytosis (CME), the major pathway by which influenza virus enters cells. However, other host factors almost certainly involved in the influenza virus CME are largely unknown. Here, we found that the four-transmembrane protein claudin-11 plays an integral part in influenza virus CME. Claudin-11 promotes the dissociation of KCa1.1 (potassium calcium-activated channel subfamily M alpha 1) from mGluR2 and, together with mGluR2, is internalized in virus-containing clathrin-coated pits (CCPs), where it regulates the depolymerization of polymerized F-actin, allowing the CCPs to mature. Importantly, over 60% of claudin-11-silenced mice survived infection with a lethal influenza virus. Our findings advance the understanding of influenza virus infection and provide a promising strategy for the development of host-based antiviral drugs.