<p>Salivary gland hypofunction is a common adverse effect in patients after radiotherapy for head and neck cancers, resulting in the dry mouth syndrome called xerostomia. Previous studies suggested that the functionality of the salivary gland is under the regulation of the circadian clock, however, the extent and scope of this regulation remains unexplored. Here, we profiled the diurnal fluctuation of gene expression in the mouse submandibular gland, and found that about 6% of the transcriptome showed rhythmic expression. We further analyzed the regulatory role of key circadian transcription factors BMAL1, NR1D1 (REV-ERBA), and DBP, which revealed a wide range of potential down-stream target genes. The circadian rhythmic transcription was disrupted upon irradiation in a process related to p53 activation and the increased production of reactive oxygen species. Modulation of the circadian clock by chemical agents including Nobiletin and SR1078 can reduce the damaging effect and improve saliva production. We propose that the salivary gland hypofunction after radiotherapy involves perturbation of the circadian rhythmic transcription, which can be partially rescued by chemical agents that improve the circadian rhythm.</p>