The ubiquitin-26S proteasome system (UPS) is a conserved protein degradation process involved in plant growth and immunity. However, whether some UPS E3 ligases directly target plant viruses in the endoplasmic reticulum (ER) remains less understood. Here, we identify an E3 ubiquitin ligase Hmg-CoA reductase degradation 1 of Nicotiana benthamiana (NbHRD1) interacting with the triple gene block (TGB) movement proteins of beet necrotic yellow vein virus (BNYVV) in the ER. The TGB proteins are ubiquitinated by NbHRD1 and then degraded by the UPS. Consequently, overexpression of NbHRD1a significantly inhibits BNYVV infection, whereas silencing of NbHRD1 promotes BNYVV infection in N. benthamiana. Moreover, NbHRD1a mainly impairs BNYVV cell-to-cell movement, rather than virus replication. Interestingly, NbHRD1 also targets the TGB proteins of potato virus X for ubiquitination and virus inhibition. Collectively, our results demonstrate that NbHRD1 is an important antiviral component targeting plant viruses with TGB movement proteins.