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Nonstructural protein 1 (NS1) is the key virulence factor of influenza A virus (IAV) that affects the replication and pathogenicity of IAV, which can be used as a promising anti-IAV target. Herein, we identify a marine derived NS1 inhibitor HDN2398 with broad-spectrum anti-IAV effects in different cell lines and female mice, superior to oseltamivir and baloxavir. HDN2398 attenuates the interferon antagonist function of NS1 by blocking NS1 dimerization and its binding to dsRNA. HDN2398 can block NS1 nucleolar localization, viral mRNA splicing and nuclear export through destroying the interaction between NS1 and nucleolin or NXF1. Phe9 and Trp187 may be required for the interaction between HDN2398 and NS1. In summary, our findings support the development of HDN2398 as a promising anti-IAV agent targeting NS1-host interaction.