Intestinal side effects have a substantial impact on patients' quality of life and constrain radiation therapy (RT) of abdominal and pelvic tumors. We aim at gaining a better understanding of the pathogenesis of intestinal radiotoxicity and identifying contributing factors. A high salt diet is common among countries of the Global North. The effects of an increased sodium-chloride (NaCl) intake on the development of intestinal side effects have not been investigated. C57BL/6 wild-type (WT) mice were fed a high salt diet (HSD) or normal salt diet (NSD) and irradiated with 12 Gy total body irradiation (TBI) or 13 Gy abdominal irradiation (ABI). Following TBI the mice received a syngeneic bone marrow transplant to reconstitute hematopoiesis. Readouts after RT included weight monitoring, histopathological analysis and assessment of intestinal epithelial barrier function. To corroborate our findings in vitro, murine organoids of the small intestine were cultivated, treated with varying NaCl concentrations (110-200 mM) and irradiated with 2 or 4 Gy. Organoid survival and growth were determined using multiple methods. Additionally, colony formation assays (CFA) of murine MC38 colon carcinoma cells were performed after stimulation with NaCl. Mechanistically, we analyzed the apoptosis rates of MC38 cells and intestinal epithelial organoids. Irradiated HSD animals showed increased acute weight loss, reduced weight regeneration, a more severe dysfunction of the intestinal barrier (enhanced FITC-dextran permeability) and increased histopathological damage when compared with NSD animals. Murine intestinal organoids and MC38 cells showed decreased survival after RT in hypernatremic conditions. Interestingly, our preliminary data show that there are no increased rates of apoptotic cells in vitro, suggesting a different mechanism affecting the increased radiosensitivity in hypernatremic conditions. Our data show a NaCl induced intensification of intestinal tissue injury following RT. These findings can potentially pave the way for investigating the effect of high salt diet on intestinal radiotoxicity in clinical trials.