Background: Gastroesophageal reflux disease accounts for more than 20% of the Western population and is a disease that is also increasing in incidence in Asian countries. Objectives: This work was aimed to assess the impact of Evodiae Fructus and Toosendan Fructus against esophageal mucosal injury with Duodenogastroesophageal Reflux Esophagitis (DGER). Materials and Methods: After inducing DGER through surgery, the group was separated (n = 8) and the drug was administered for 2 weeks: normal rats (Normal), Water-treated DGER (Control), Evodiae Fructus 200 mg/kg-treated DGER (EF), and Toosendan Fructus 200 mg/kg-treated DGER (TF). Results: The administration of EF and TF significantly protected the esophageal mucosa. Furthermore, the content of bilirubin, glutamate oxaloacetate transaminase, and glutamate pyruvate transaminase in serum decreased in EF and TF. In addition, those significantly regulated the protein expression of Janus kinase (JAK)/signal transducer and activator of transcription (STAT), AP-1/MAPK, mtrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP), and tight junction. Conclusion: Taken together, the administration of EF and TF significantly protected the esophageal mucosa of reflux esophagitis, and in particular, the esophageal mucosa protective effect was better in EF. Furthermore, EF and TF inhibited the JAK/STAT and AP-1/MAPK pathway, and EF significantly modulated the expression of MMP/TIMP. These results show the potential of EF as a material for DGER by alleviating inflammation and improving esophageal function.