Tamoxifen was approved for breast cancer chemoprevention in high-risk women despite its side effects, especially on gastrointestinal tract. Therefore, this study aimed to demonstrate the therapeutic and protective properties of sodium butyrate (SB; 300 mg/kg body weight) against the small intestine injury induced by tamoxifen citrate (TC; 40 mg/kg body weight) in rats. Forty-nine male Wistar rats were randomly allotted into 5 main groups: the control group (where the rats received oral saline), SB group, TC group, SB-TC group (where SB was given before TC), and TC-SB group (where TC was given before SB). SB in TC-SB group increased the regenerative capacity of damaged intestinal tissue, decreased significantly (P<0.05)the level of intestinal malondialdehyde, and increased significantly (P<0.05) the reduced glutathione level and the activities of glutathione peroxidase, catalase, and superoxide dismutase in the intestinal tissues compared with the TC-treated group. SB also suppressed the proinflammatory cytokine response and reduced oxidative DNA damage in the intestinal tissues of the TC-SB group compared with the TC-treated group. In conclusion, this study suggested that SB reduced the harmful effects of TC on the intestinal tissues of the rats by reducing oxidative stress and decreasing the generation of proinflammatory cytokines.