Enteroviruses (EVs), encompassing over 200 sero/genotypes, cause diseases ranging from mild illness to severe systemic infections. Galectin-9 (Gal-9) is an immunomodulatory lectin implicated in various viral infections, yet its role in EVs remains unexplored. Here, we identify Gal-9 as a novel host restriction factor against a broad spectrum of EVs, including EV-A71, EV-D68, and Coxsackievirus B2. LGALS9 deficiency increased viral replication in cells and pathogenicity in a mouse model of