Intestinal damage is one of the major toxic effects of methotrexate (MTX). The aim of this study was to evaluate the protective effects of quercetin on MTX-induced small intestine damage in rats. Thirty-six male Wistar rats were randomly allocated into four equal groups. The first group was the control. The second group, only quercetin (15 mg/kg) was administered intraperitoneally for 15 consecutive days. The third group, MTX was applied as a single dose (20 mg/kg) intraperitoneally at fifteenth day. The fourth group, quercetin was given intraperitoneally in addition to MTX application until the rats were killed. All animals were sacrificed 4 days after the MTX injection for histopathological examination and the assay for serum total antioxidant activity (TAA), tissue reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) levels. Microscopically, jejunal tissues of the MTX treated group showed severe villus shortening and blunting, inflammatory cell infiltration and hemorrhage in lamina propria, as well as epithelial cell necrosis, however, administration of quercetin alleviated the jejunal damage. Levels of TAA, GSH, SOD, CAT, GPx and GR decreased in the MTX received group, but increased significantly (P=0.00) in the quercetin+MTX groups. Quercetin significantly (P=0.00) decreased MDA levels which was increased by MTX treatment. The results showed that quercetin due to its antioxidant properties may protect the small intestine of rats from MTX-induced damage.