Background: Patients with diabetes mellitus (DM) are at significant risk for variable complications particularly, gastrointestinal tract disorders such as peptic ulcers. Omega-3 polyunsaturated fatty acids (PUFAs) and leptin can help tissue healing through their antiinflammatory, antidiabetic, and antioxidant effects. This work compares ω-3 PUFAs and leptin impact on gastric ulcers in diabetics. Methods: 36 rats were divided equally into negative control (n = 9) and Streptozotocin-induced type-II DM (n = 27) groups. The latter group was subdivided into three equal subgroups (n=9): diabetic control, diabetic with leptin, and diabetic with ω-3 PUFAs. A single oral indomethacin dose induced the ulcer by the end of the experiment. We assessed gastric mucosa gross appearance, histopathological changes and biochemical parameters.Results: Chronic administration of leptin and ω-3 PUFAs remarkably ameliorated gastric ulcer index, ulcer protection percentage, the gastric expression of reduced glutathione, cholecystokinin and endothelial nitric-oxide synthase genes, and significantly decreased the expression of proton pump gene and cyclo-oxygenase-2 enzyme activity. Conclusion: This work found that leptin and ω-3 have antacid, anti-inflammatory, and antioxidant effects against indomethacin-induced gastric ulcers in diabetic rats, with a more potent effect of ω-3. We hypothesize that concomitent use of both would have an augmented anti-ulcer results.