Gastric ulcers represent a worldwide health problem, characterized by erosions with different degrees in the gastrointestinal mucosa. In the current study, we explore the protective effects of the extract of apple seeds (Malus domestica, family: Rosaceae), regarded as environmental wastes, against indomethacin-induced gastric ulcers in rats. The chemical composition of the seeds extract was investigated through liquid chromatography high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS). The metabolomics profiling resulted in identification of 17 compounds (1–17) of different chemical classes. The gene ontology analysis demonstrated that the total extract of M. domestica seeds possess an antiulcer activity through PI3K-Akt signaling pathway as the top identified signaling pathway. The present research work evidenced the reuse of apple seeds waste as an effective therapy to treat NSAIDs-induced gastric ulcer, attributed to its anti-inflammatory and antioxidant properties. It is important to note that the extract does not cause the undesirable effects of traditional antisecretory drugs.