Nonsense-mediated mRNA decay (NMD) is a critical RNA quality control system in eukaryotes, also playing a role in defending against viral infections. However, research has primarily focused on nonsegmented viruses. To investigate the interaction between NMD and segmented RNA viruses, we used cucumber mosaic virus (CMV), which possesses a tripartite, single-stranded, positive-sense RNA genome. Agroinfiltration assays were performed to assess how CMV RNA segments, or their variants, respond to NMD. We found that CMV genomic segments (RNAs 1-3) exhibit distinct responses to NMD. Specifically, RNA3, which serves as the translation template of the movement protein (MP), is selectively degraded by NMD, unlike RNA1 and RNA2, which encode viral replicase components. This degradation is triggered by the coat protein (CP) sequence and can be mitigated by the trans-expression of the 1a replicase or CP. The 1a protein requires its specific interaction with the Box-B motif of RNA3 to avoid NMD. Importantly, compromising NMD reduces CMV infection during the early stages, suggesting that NMD-mediated RNA3 degradation facilitates initial viral replication. This is supported by observations that MP expression in trans negatively regulates viral RNA replication. We propose a model to illustrate the molecular interplay between NMD and CMV, emphasising the implications of genomic segmentation in NMD-virus interactions.