SF3B4, a splicing factor known to regulate mRNA expression and function, is upregulated in various cancers. Despite its potential significance, the mechanisms through which SF3B4 regulates nonsense-mediated mRNA decay (NMD) and cancer cell senescence remain poorly understood. This study explores the underlying mechanisms by which SF3B4 modulates mRNA stability through the NMD pathway and elucidates its role in switching cancer cells between growth and senescence. We demonstrate that SF3B4 deficiency leads to decreased cancer cell proliferation, increased senescence-associated β-galactosidase (SA-β-Gal) activity, p53-independent upregulation of p21 expression, and ultimate induction of cell senescence. We further show that SF3B4 recruits essential NMD factors, including UPF1, MAGOH, and RNPS1, which facilitate mRNA decay of the crucial senescence regulator, p21. Conversely, SF3B4 depletion results in the dissociation of these factors from the 3'UTR of p21 mRNA, thereby enhancing its stability. Collectively, our results suggest that SF3B4 critically regulates p21 expression at the post-transcriptional level, providing insights into the novel role of SF3B4 in regulating p21 mRNA stability, interacting with key NMD factors, and modulating cancer cell senescence.