The highly pathogenic avian influenza (HPAI) A/H5N1 virus hijacks host cellular machinery to complete its life cycle; identification of the host factors involved in viral replication may facilitate antiviral drug development. Here, we first characterize a metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), and showed that it plays a crucial role in H5N1 viral replication. We found that H5N1 infection upregulated NDRG1 mRNA and protein expression. Overexpression of NDRG1 released approximately 4-fold more virions compared to the control group, whereas knockdown of NDRG1 resulted in a drop in viral RNA and protein production. Further investigation revealed that NDRG1 facilitated HPAI A/H5N1 viral replication by suppressing the canonical NF-κB signaling pathway. Furthermore, our results also showed that the NDRG1 mRNA level was mainly stimulated by M1 and PB1 viral proteins. Overall, our results suggest that NDRG1 plays a positive role in HPAI replication by suppressing the canonical NF-κB signaling pathway.