Background: Nowadays, the use of plant extracts is increasing in the world for the prevention and treatment of ulcer. Objective: The objective of this study was to explore the underlying mechanism of action of fisetin on ethanol-induced gastric ulcer model. Materials and Methods: In this study, gastric mucosal lesions were induced by ethanol in rats. Five groups of rats were formed based on the treatment administered: model group (model), omeprazole (40 mg/kg) group (omeprazole), high-dose fisetin group (100 mg/kg, H-fisetin), medium-dose fisetin group (50 mg/kg, M-fisetin), and low-dose fisetin group (25 mg/kg, L-fisetin). Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels were assessed in serum. The expression of peroxisome proliferator-activated receptor (PPAR)-γ, nuclear factor-kappa B (NF-κB), and p38-mitogen-activated protein kinase (p38-MAPK) in the gastric mucosa was also measured. Results: In the case of the high-dose fisetin group, the level of TNF-α, IL-1β, and IL-6 decreased from 9.57 pg/mL to 5.19 pg/mL, from 0.59 pg/mL to 0.27 pg/mL, and from 37.96 pg/mL to 21.09 pg/mL, respectively. In the case of the omeprazole group, the level of TNF-α, IL-1β, and IL-6 decreased to 4.38 pg/mL, 0.27 pg/mL, and 18.58 pg/mL, respectively. The expression of PPAR-γ protein in the high-dose fisetin and omeprazole groups was about 1.5 times higher than that in the model group. Compared with the model group, the expression of NF-κB protein reduced to 0.34 level and 0.47 level in the omeprazole and high-dose fisetin groups, respectively. Compared with the model group, the expression of p38-MAPK protein reduced to 0.55 level and 0.68 level in the omeprazole and high-dose fisetin groups, respectively. Conclusion: Fisetin might relieve the symptoms of ethanol-induced gastric ulcer in rats through the regulation of NF-κB pathway.