Gastric ulcer (GU) is a worldwide gastrointestinal disorder associated with NSAID use. Recently, amentoflavone proved to be a potent autophagy modulator, antioxidant, anti-inflammatory, and anti-apoptotic agent. Eight-week-old male Wistar rats received amentoflavone orally for 14 days at 25, 50, or 100 mg/kg/day. On day 14 of treatment, GU was induced by a single oral instillation of 100 mg/kg indomethacin, one hour after the last treatment. Amentoflavone dose-dependently alleviated indomethacin-induced GU, as demonstrated by repression of gastric mucosa pathological manifestations (ulcer index, ulcer surface area, histopathological deviations, and score) and increased ulcer inhibition percentage. These protective effects were due to the enhancement of gastric mucosa autophagy, as demonstrated by increased levels of beclin-1, MAP1LC3B, and CTSD, and reduced expression of p62 (SQSTM1). In addition, amentoflavone modulated the AMPK/mTOR pathway by increasing p-AMPK and reducing mTORC1 levels. Moreover, it hindered the redox aberrations by reducing MDA level and enhancing SOD activity, GSH level, and Nrf2/HO-1 cascade. Furthermore, a decrease in caspase-3 levels, Bax/Bcl-2 ratio and an increase in Bcl-2 expression suggest inhibition of the apoptotic process. Additionally, amentoflavone suppressed gastric mucosal inflammation by decreasing IL-1β, TNF-α, IFN-γ levels, IL-4, IL-6 mRNA expressions and MPO activity, and increasing IL-10 mRNA expresion. Therefore, amentoflavone could consider a promising natural agent protecting against indomethacin-induced GU.