AIM: To investigate the possible mechanisms by observing the effects of sodium butyrate on the blood-brain barrier and cognitive function after intestinal ischemia/reperfusion in rats. METHODS: SD rats were randomly divided into 4 groups of 12 rats each, (1) sham-operated group (the Sham group); (2) intestinal ischemia/reperfusion group (the II/R group); (3) intestinal ischemia/reperfusion+sodium butyrate group (the NaB group): gavage of NaB 500 mg·kg-1·d-1 for 1 week before modeling; (4) intestinal ischemia/reperfusion+sodium butyrate+ITSA-1 group (the ITSA-1 group): NaB 500 mg·kg-1·d-1 gavage 1 week before modeling+ITSA-1 0.5 mg/kg intraperitoneal injection in the first 5 d, 3 d and 1 d. Intestinal mucosal injury was evaluated by HE staining. Morris water maze test evaluated the cognitive function of rats. The microstructure of the blood-brain barrier was observed by transmission electron microscope. The levels of inflammatory cytokines IL-1β, IL-6, TNF-α, Claudin5, ZO-1, and MMP-9 in brain tissue were detected by ELISA. Western blotting detected Claudin5, ZO-1, CypA, and MMP-9 levels. RESULTS: Compared with the Sham group, Chiu's score in the II/R group was increased (P<0.001). The swimming distance was increased (P<0.05), the proportion of the non-platform quadrant was increased (P<0.001), and the incubation period was prolonged (P<0.05). The microstructure of the blood-brain barrier was changed under the transmission electron microscope. The inflammatory cytokines IL-1β, IL-6, and TNF-α were increased (P<0.001), the expressions of CypA and MMP-9 were increased (P<0.01), and the expressions of Claudin5 and ZO-1 were decreased (P<0.01, P<0.001). Compared with the II/R group, neuroinflammation, and blood-brain barrier damage were reduced, and cognitive function was improved in the II/R+NaB group. The above injuries in group II/R+NaB+ITSA-1 were similar to those in group II/R. CONCLUSION: Sodium butyrate can ameliorate II/R-induced neurocognitive dysfunction in rats by alleviating blood-brain barrier damage, possibly related to inhibiting the CypA/MMP-9 pathway.