Background: Reflux esophagitis (RE) is a type of gastroesophageal reflux disease (GERD) that severely reduces the quality of life. The Cudrania tricuspidata (C. tricuspidata) fruit is commonly used in food and has medicinal values such as clearing heat, relaxing muscles, and collaterals. Objectives: We evaluated fermented C. tricuspidata fruit extract (FCt) in this study. We measured its anti-inflammatory activity by using LPS-induced Raw 264.7 cell model and evaluated its role in improving acute reflux esophagitis in rats. Materials and Methods: The gastrodin content before and after fermentation was determined. NO production in cell supernatant was measured using the Griess reagent method, and TNF-α and IL-1β secretion was detected using the Quantikine ELISA kit. Expression level of proteins was measured by western blotting. Immunofluorescence assay was used for confirming the activation of NF-κB. The protective effects of FCt on RE were conducted in the rat RE model by observing esophageal tissue damage and inflammatory proteins expression levels in the esophagus. Results: The results showed that the content of gastrodin in C. tricuspidata fruit increased upon fermentation. FCt inhibited the production of NO, TNF-α, and IL-1β and the activation of NF-κB. In addition, FCt significantly improved esophageal tissue damage caused by acid reflux and inhibited the expression of inflammatory proteins iNOS and COX-2 in esophageal tissue. The term of tight junction (claudin-4) is increased to maintain the barrier function of cell tissues. Conclusion: We suggested that FCt could consider being a candidate medicine material for treating RE.