Background: Reflux esophagitis (RE) is one of the gastroesophageal reflux diseases that seriously affect the daily life of patients. Magnolia sieboldii K. Koch has been used as a traditional Chinese herbal medicine for stomach pain relief and deworming and has various physiological activities. Objective: The objective is to investigate the anti-inflammatory and protective effects of the ethanol extract of M. sieboldii buds (MsE) on RE. Materials and Methods: The different concentrations of MsE were used to determine the anti-inflammatory effects on lipopolysaccharide (LPS)-induced cells. In addition, the treatment of MsE on experimental RE rats were used for determining the protective effects of MsE on RE. Results: M. sieboldii treatment effectively inhibited LPS-induced nitric oxide (NO) production, protein expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) by regulating the activation of nuclear factor-κB (NF-κB) and C-Jun N-terminal kinase/mitogen-activated protein kinase in cells. Furthermore, M. sieboldii treatment significantly ameliorated esophageal tissue damage caused by gastric acid reflux, as well as inhibited the expression of COX-2, TNF-α, and interleukin-1 beta in esophageal tissues through inhibition the activation of NF-κB. Conclusion: We suggested that the ethanol extract of M. sieboldii could consider being an alternative medicine material for treating RE.