<p>Radiation-induced intestinal injury is characterized by structural and functional impairment of intestinal tissues following exposure to ionizing radiation, and homeostasis of the enteric nervous system is essential for preserving normal gastrointestinal physiological function. While amifostine confers radioprotection primarily through free radical scavenging and modulation of the intestinal microbiota, its regulatory effects on the enteric nervous system remain unexplored. In this study, a mouse model of radiation-induced intestinal injury was established by targeted abdominal irradiation with ⁶⁰Co γ-rays, and small intestinal motility assessments, histopathological staining, and immunofluorescence histochemistry were performed to evaluate structural injury, epithelial integrity, and morphological changes in the myenteric plexus. The results showed that amifostine significantly mitigated intestinal tissue injury, preserved epithelial integrity, increased survival, and substantially improved small intestinal dysmotility in irradiated mice. This protective effect on motility was associated with selective enteric nervous system regulation, specifically the suppression of enteric glial cell activation and the selective prevention of inhibitory nitrergic neuron loss, whereas no significant alterations were detected in the numbers of excitatory cholinergic or peptidergic neurons. In conclusion, amifostine alleviates ionizing radiation-induced small intestinal hyperperistalsis (propulsion) by remodeling the structural homeostasis of the enteric nervous system.</p>