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Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD eliminates aberrant mRNAs with premature termination codons to surveil transcriptome integrity. Furthermore, NMD fine-tunes gene expression by destabilizing RNAs with specific NMD features. Thus, by controlling the quality and quantity of the transcriptome, NMD plays a vital role in mammalian development, stress response, and tumorigenesis. Deficiencies of NMD factors result in early embryonic lethality, while the underlying mechanisms are poorly understood. SMG5 is a key NMD factor. In this study, we generated an <i>Smg5</i> conditional knockout mouse model and found that <i>Smg5</i>-null results in early embryonic lethality before E13.5. Furthermore, we produced multiple lines of <i>Smg5</i> knockout mouse embryonic stem cells (mESCs) and found that the deletion of <i>Smg5</i> in mESCs does not compromise cell viability. <i>Smg5</i>-null delays differentiation of mESCs. Mechanistically, our study reveals that the c-MYC protein, but not <i>c-Myc</i> mRNA, is upregulated in SMG5-deficient mESCs. The overproduction of c-MYC protein could be caused by enhanced protein synthesis upon SMG5 loss. Furthermore, SMG5-null results in dysregulation of alternative splicing on multiple stem cell differentiation regulators. Overall, our findings underscore the importance of SMG5-NMD in regulating mESC cell-state transition.