Upper gastrointestinal bleeding from erosive gastritis remains associated with high mortality in septic or postoperative patients. While stress ulcer bleeding has declined, it still occurs in septic patients and is considered a manifestation of intestinal failure within multi-organ failure syndrome. The integrity of the gastric mucosal barrier plays a crucial role in protection against this condition. Somatostatin (SS) appears as a biomolecule with cytoprotective properties. We aimed to investigate whether SS treatment protected the gastric mucosa in a rat model of lipopolysaccharide (LPS)-induced sepsis. Rats received LPS (10 mg/kg) intraperitoneally, followed by saline or SS (200 μg/kg; 5 mL/kg) treatment after 30 min (early treatment group) or 120 min (late treatment group). Control rats received only saline. Two hours after saline or SS administration (total procedure duration of 150 or 240 min), gastric lavage, gastric mucosa, and plasma samples were collected for analysis. SS treatment mitigated the LPS-induced gastric mucosal barrier disruption preserving phosphatidylcholine (PC) levels, as well as decreasing leukocyte infiltration marker myeloperoxidase (MPO), inflammation-related enzyme phospholipase A2 (PLA2), and lipid peroxidation indicator malondialdehyde (MDA). SS also reduced arachidonic acid-related metabolites thromboxane B2 (TXB2) and leukotriene B4 (LTB4) while increasing prostaglandin I2 (PGI2). SS treatment effectively maintained gastric mucosal integrity, reducing inflammation, and modulating arachidonic acid metabolites. These findings suggest that SS may serve as a therapeutic agent for preserving gastric mucosal integrity and reducing inflammation in LPS-induced gastric injury.