The utilization of plants with therapeutic properties in traditional medicine has a longstanding practice. Among them, the well-known Allium cepa L. commonly known as onion has been valued for its anti-inflammatory and antioxidant potential in the treatment of various ailments, including gastric ulcers.This study investigated the gastroprotective potential of red onion peel extract and its fractions in a rat model of ethanol-induced gastric ulcer. Moreover, their phytochemical profiles were compared to identify the active metabolites.Mass spectrometry-based metabolomics and chemometrics were performed for phytochemical analysis. Ethanol-induced gastric ulcer model was used to assess the gastroprotective activity. Nine groups of rats were allocated as follows: Group 1 was the normal control; Group 2 rats were used as a positive control/model and received 1 mL of absolute ethanol; and Group 3 rats were treated with famotidine at a dose of 20 mg/kg orally. Group 4 and 5 rats were treated with total acidified ethanolic extract (T1, T2). Group 6 and 7 rats were treated with anthocyanins-rich fractions (P1, P2). Groups 8 and 9 were the flavonoids-rich fraction (S1, S2) treatment. Prior to scarification, the ulcer index in mm was obtained from gastric tissues photographed beside a ruler with further analysis using ImageJ software.Seventy key major and discriminatory metabolites were identified including flavonoids, anthocyanins, phenolic acids, and miscellaneous compounds. The examined extract and its fractions significantly reduced the ulcer index and inflammatory cytokines via downregulating HMGB-1/NF-κB. Also, they augmented the expression of Nrf2/HO-1 and reduced NOX1/4 mRNA expression. Moreover, there was a significant reduction in the oxidative stress and apoptotic biomarkers as well as a noticeable enhancement in histopathological changes of the stomach tissues.Red onion peels have a promising dose dependent gastroprotective potential in alcohol-induced ulcers via modulating Nrf2/HO-1 and HMGB-1/NF-κB trajectories. This highlights the potential of red onion peels in treating gastric ulcers.