Nearly 25% of gastric ulcer (GU) instances globally are induced via nonsteroidal anti-inflammatory drugs (NSAIDs). Infliximab (Inflix), a monoclonal antibody, is widely utilized to medicate autoimmune disorders and chronic inflammatory disorders. This investigation aimed to determine if Inflix could prevent indomethacin (IND)-induced GU while examining potential protective mechanisms, such as the NF-κB/MAPK signaling pathway. Male albino rats received Inflix (5 and 7 mg/kg, intraperitoneally) on the fifth day, fasted for 24 h, and were exposed to IND (100 mg/kg, orally) for ulcer induction on the eighth day. The study showed that IND caused GU in macroscopic and histopathological manifestations. Pretreatment with Inflix improved gastric tissue damage in histopathological and macroscopic manifestations in a dose-dependent manner. Moreover, Inflix pretreatment increased the IND-affected decline in stomach prostaglandin E2 (PGE2) levels. Additionally, Inflix exerted antioxidant, anti-inflammatory, and anti-apoptotic effects by lowering oxidative stress markers, pro-inflammatory markers, and apoptotic markers in a dose-dependent approach. It was demonstrated that Inflix reduced the mitogen-activated protein kinase (MAPK) and the nuclear factor kappa B (NF-κB) p65 induced by IND-induced GU. Inflix exerts a gastro-protective effect via antioxidant, anti-inflammatory, and anti-apoptotic actions, which could be associated with modulating the NF-κB and MAPK cascades.