Gastroesophageal reflux disease (GERD) is a gastrointestinal disorder in which stomach contents reflux into the esophagus, causing complications such as mucosal damage. The purpose of this study was to determine the effect of Rhei Rhizoma and Scutellariae Radix mixture (RS) in chronic acid reflux esophagitis (CARE), one of the GERD. After inducing reflux esophagitis through surgery, the group was separated and the drug was administered for 2 weeks; Normal rats (Normal, n=8), chronic acid reflux esophagitis rats (Control, n=8), tocopherol 30 mg/kg-treated chronic acid reflux esophagitis rats (Toco, n=8), Rhei Rhizoma and Scutellariae Radix mixture 100 mg/kg-treated chronic acid reflux esophagitis rats (RSL, n=8), Rhei Rhizoma and Scutellariae Radix mixture 200 mg/kg-treated chronic acid reflux esophagitis rats (RSH, n=8). Gross lesion of esophageal mucosa after RS treatment showed a superior enhancement compared with that of Control group. Additionally, RS significantly decreased the levels of MPO and MDA, effectively inhibited NADPH oxidase, and regulated the expression of the AMPK/LKB1/NF-κB pathway. Moreover, it significantly increased the expression of tight junction proteins. Taken together, RS not only alleviates inflammation of the esophageal mucosa via the AMPK/LKB1/NF-κB pathway by reducing oxidative stress, but also improves esophageal function by modulating tight junction proteins.