Purpose Rhei Rhizoma (RR) is one of the herbal medicines traditionally used to treat diverse inflammatory diseases. The present study was undertaken to elucidate the antioxidant and anti-inflammatory activities of Rhei Rhizoma on experimental reflux esophagitis (RE) in rats. Methods The antioxidant activity of RR in vitro was measured in terms of radical scavenging capacity such as DPPH and ABTS. RE was produced by ligating both the pylorus and the transitional junction between the forestomach and the corpus. Rhei Rhizoma (125 and 250 mg/kg) were administered every day for 7 days, and its effect was estimated on comparison with RE control and normal rats. Results RR scavenged DPPH and ABTS effectively and IC50ofDPPH and ABTS radical scavenging activity of RR were 4.8 μg/ml and 15.75 μg/ml. The administration of RR decreased the elevated serum ROS in RE control rats. The RE control rats exhibited the down-regulation of antioxidant-related proteins such as Nrf2 and HO-1expression levels in the esophagitis; however, the level in the RR-treated RE rats was significantly higher than that in the RE control rats. Moreover, RE control rats exhibited the up-regulation of the protein expression related to oxidative stress at the esophagitis, but RR administration significantly reduced the expression of inflammatory proteins through the MAPK-independent signaling pathways. The expression of inflammatory mediators and cytokines by NF-κB activation was modulated through blocking the degradation of IκBα. In addition, the oral administration of RR regulated the gastric mucosal damage in RE rats. Conclusion The administration of Rhei Rhizoma effectively ameliorates the inflammatory damage of esophageal mucosa through radical scavenging activity and the activation of the Nrf2/HO-1 pathway.