Porcine circovirus type 3 (PCV3) is an emerging pathogen that causes porcine dermatitis, nephropathy syndrome-like symptoms, multisystemic inflammation, and reproductive failure. The PCV3 capsid (Cap) protein interacts with DDX21, which functions mainly through controlling interferon (IFN)-β levels. However, how the interaction between DDX21 and PCV3 Cap regulates viral replication remains unknown. In the present study, upon shRNA-mediated DDX21 depletion in PK-15 cells, we observed impaired PCV3 proliferation via a lentivirus-delivered system, as indicated by reduced replicase (Rep) protein levels and viral titers. Furthermore, DDX21 negatively regulated IFN-β and interferon-stimulated gene (ISG) levels, promoting PCV3 replication. Mechanistically, PCV3 Cap co-localized and interacted with DDX21, and the nuclear localization signal (NLS) of PCV3 Cap and 763GSRSNRFQNK772 at the C-terminal domain (CTD) of DDX21 were indispensable to the interaction. Moreover, PCV3 infection prevented the repression of DDX21 to facilitate its pro-viral activity. Taken together, these results show that DDX21 promotes PCV3 replication by binding to the PCV3 Cap protein and prohibiting IFN-β response, which provides important insight on the prevention and control of PCV3 infection.