Rebamipide (Reba) is a well-known gastroprotective agent. However, its potential protective efficacy against intestinal ischemia/reperfusion (I/R)-induced liver injury remains elusive. Therefore, this study aimed to assess the modulatory effect of Reba on SIRT1/β-catenin/FOXO1-NFκB signaling cascade. Thirty-two male Wistar albino rats were randomized into four groups: G1 (sham): rats were subjected to surgical stress without I/R, GII (I/ R): rats were subjected to 60 min/4-h I/R, GIII (Reba + I/R): rats received Reba 100 mg/kg/day, p.o. for three weeks, then were subjected to 60 min/4-h I/R, and GIV (Reba + EX527 + I/R): rats received Reba (100 mg/kg/ day p.o.) + EX527 (10 mg/kg/day, ip) for three weeks before I/R. Reba pretreatment decreased the serum levels of ALT and AST, improved I/R-induced histological alterations of both intestine and liver, increased hepatic Silent information regulator 1 (SIRT1) expression/content, β-catenin expression/immunoreactivity, and FOXO1 expression, while suppressed NF-κB p65 expression/protein content. In addition, Reba increased hepatic total antioxidant capacity (TAC), while suppressed malondialdehyde (MDA), tumor necrosis factor (TNFα), and caspase-3 activity. Furthermore, Reba inhibited BAX expression, while upregulated Bcl-2 expression. Reba exhibited a plausible protective effect against intestinal I/R-mediated liver injury by modulating SIRT1/β-catenin/FOXO1-NFκB signaling mechanisms.