Cell-intrinsic restriction factors (CIRFs) negatively regulate plant virus infections and represent valuable resources for breeding virus-resistant crops. However, the potential for ribosomal proteins to function as CIRFs and the underlying mechanisms remains elusive. Our previous work demonstrated that the Nicotiana benthamiana chloroplastic ribosomal protein of the large subunit 1 (NbRPL1) promotes the infection of tobacco vein banding mosaic virus (TVBMV) by antagonizing the NbBeclin1-mediated degradation of the viral RNA-dependent RNA polymerase, NIb. Continuing this line of research, we explored the role of another nonchloroplastic ribosomal protein, large ribosomal protein 4 (RPL4), in TVBMV replication. We found that TVBMV NIb interacts with NbRPL4; however, the NIb proteins of 2 other related potyviruses, potato virus Y (PVY) and turnip mosaic virus (TuMV), did not interact with NbRPL4. Overexpression of NbRPL4 inhibited, whereas its downregulation promoted, TVBMV replication. NbRPL4 did not affect PVY or TuMV replication. The nuclear-cytoplasmic distribution of NbRPL4 positively correlated with its antiviral effect on TVBMV replication. NbRPL4 interfered with NbXPO1-mediated nuclear export of the NIb protein, subsequently affecting the translocation of NIb into the viral replication compartment. Our work indicates that NbRPL4 functions as a restriction factor for TVBMV by inhibiting NbXPO1-mediated nuclear export of NIb in a virus-specific manner.