Eukaryotic cells rely on the DNA damage response (DDR) to monitor and repair DNA damage, thereby maintaining genomic stability. When DDR-related genes are mutated or dysfunctional, this balance is disrupted, promoting tumourigenesis, progression and resistance to therapy. Recent work, including large-scale genetic and molecular analyses, have identified RNA-binding proteins (RBPs) as major players in maintaining genome stability. RBPs regulate the expression of many critical proteins at the post-transcriptional level and are directly involved in DNA repair. Therefore, this review outlines how RBPs dynamically regulate the DDR pathway through post-transcriptional regulation, non-coding RNA interactions, clarifies the functions of key RBPs in DNA repair, cell cycle checkpoints and apoptosis, and summarizes how RBPs can contribute to radiotherapy resistance and chemoresistance by enhancing repair efficiency or inhibiting apoptosis. This provides new targets for overcoming cancer therapeutic resistance, promotes precision treatment strategies based on RBPs functional heterogeneity, and facilitates the clinical translation of novel RNA-based therapeutics.