Persistent DNA damage induces profound alterations in gene expression that, in turn, influence tissue homeostasis, tumorigenesis, and cancer treatment outcome. However, the underlying mechanism for gene expression reprogramming induced by persistent DNA damage remains poorly understood. Here, using a highly effective bioluminescence-based reporter system and other tools, we report that persistent DNA damage inhibits nonsense-mediated RNA decay (NMD), an RNA surveillance and gene-regulatory pathway, in noncycling cells. NMD suppression by persistent DNA damage required the activity of the p38 MAPK. Activating transcription factor 3 (ATF3), an NMD target and a key stress-inducible transcription factor, was stabilized in a p38- and NMD-dependent manner following persistent DNA damage. Our results reveal a novel p38-dependent pathway that regulates NMD activity in response to persistent DNA damage, which, in turn, controls ATF3 expression in affected cells.