Radiation-induced intestinal injuries (RIII) commonly occur in patients who suffer from pelvic or abdominal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant, and the radioprotective role of Nrf2 is found in bone marrow, lung, and intestine, etc. Here, we investigated the effect of knockout on radiation-induced intestinal injuries using knockout () mice and wild-type () C57BL/6J mice following 13 Gy abdominal irradiation (ABI). It was found that knockout promoted the survival of irradiated mice, protected the crypt-villus structure of the small intestine, and elevated peripheral blood lymphocyte count and thymus coefficients. The DNA damage of peripheral blood lymphocytes and the apoptosis of intestinal epithelial cells (IECs) of irradiated mice were decreased. Furthermore, compared with that of mice, knockout increased the number of intestinal stem cells (ISCs) and their daughter cells including Ki67⁺ transient amplifying cells, Villin⁺ enterocytes, and lysozyme⁺ Paneth cells. Nuclear factor-κB (NF-κB) was accumulated in the crypt base nuclei of the small intestine, and the mRNA expression of NF-κB target genes , , and of the small intestine from irradiated mice were increased. Collectively, knockout has the protective effect on small intestine damage following abdominal irradiation by prompting the proliferation and differentiation of intestinal stem cells and activation of NF-κB.