Influenza virus infection causes substantial morbidity and mortality worldwide. The limited efficacy of oseltamivir in delayed treatment， coupled with the increasing incidences of oseltamivir-resistant strains， calls for next-generation of antiviral drugs. In this study， we discovered NMS-873， an allosteric and specific p97 inhibitor， as a broad-spectrum influenza antiviral through forward chemical genomics screening. NMS-873 shows potent antiviral activity with low-nanomolar ECs against multiple human influenza A and B viruses， including adamantine-， oseltamivir-， or double resistant strains. Our data further showed that silencing of p97 via siRNA or inhibiting p97 by NMS-873 both inhibited virus replication and retained viral ribonucleoproteins (vRNPs) in the nucleus， confirming p97 is the drug target. Mechanistic studies have shown that the nuclear retention of vRNP with NMS-873 treatment is a combined result of two effects: the reduced viral M1 protein level (indirect effect)， and the disruption of p97-NP interactions (direct effect). Taken together， our results suggest that p97 could be a novel antiviral target and its inhibitor， NMS-873， is a promising antiviral drug candidate.