Cudrania tricuspidata has been used in East Asia as a folk medicine for symptoms such as inflammation, allergy, and gastritis. Administration of C. tricuspidata extract to pylori-ligated rat stomachs reduces gastric acid secretion and alleviates esophagus damage caused by gastric reflux. Therefore, in this study we aimed to investigate whether C. tricuspidata extracts inhibit reflux esophagitis by blocking H2 histamine receptor (H2R). Dimaprit, a H2R specific agonist, induced intracellular cyclic adenosine monophosphate (cAMP) production in U937 cells. Pretreatment with C. tricuspidata extracts significantly blocked dimaprit-induced cAMP production in a concentration-dependent manner. To extracted C. tricuspidata with different ethanol concentrations to determine the optimum method. We found that the 70% ethanol extract showed the most potent H2R antagonistic effect against dimaprit-induced cAMP production. However, water extract did not show any H2R blocking effect. These findings suggest that C. tricuspidata extracted using ethanol specifically inhibits gastric acid secretion and reduces esophageal injury by blocking H2R in a competitive manner. Therefore, C. tricuspidata extracts may be used in food or medicine to prevent H2R-related diseases, such as gastric hyperacidity and reflux esophagitis.