A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative in order to prevent, alleviate or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses, while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1,5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, twice daily in 12 hours intervals, in 2, 3 or 4 fractions. Acute cell death was examined at 4.5 hours post-irradiation, and histological changes at six weeks post-irradiation. Another group was given 4 fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At six weeks post-irradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, while the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months post-irradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury.