Background: Gastric ulcer is also known as stomach ulcer which is complex with multifactor-associated disease and shows high prevalent worldwide. It affects most of the people around the world, and the initiation and progression of the disease are due to the imbalance in the destructive and defensive mechanism and associated factors present in the mucosa of gastric. The current study is interested to evaluate the ethanolic extract of Sargassum fusiforme polysaccharides (SFPee) toward gastric ulcer induced by ethanol in rat model. Materials and Methods: S. fusiforme is a Chinese pharmacopeia and used as a medicinal ingredient. It contains polysaccharides, phlorotannins, and meroterpenoids which are the major contributors for its pharmacological properties. While the polysaccharides are the predominant ingredients, which account for 40%–60% of the algae dry weight. S. fusiforme polysaccharides show a potent antioxidation, anticancer, antiaging, and anticlotting function and thus promote health benefits. However, the mechanisms behind its pharmacological properties remain largely unknown. Here, we assessed the SFPee ameliorative effects on gastric ulcer induced by ethanol in male Wistar rats. We are also interested to identify the molecular machinery involvement of antigastric ulcer property of SFPee in gastric ulcer-induced rats. Results: Based on the investigation, the role of SFPee on gastric ulcer on various molecules, oxidative stress markers, antioxidant enzymes, the expression of nuclear factor-kappa B, IκB, nitrotyrosine, cyclooxygenase-2, and the assessment of the inflammatory response. Conclusion: Our results show that SFPee exhibited significant anti-inflammatory and antioxidant properties against ethanol-induced gastric ulcer by altering various molecules involved in the gastric ulcer initiation.