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Gastric ulcers are a common clinical presentation affecting anyone, regardless of their age or gender. Nanoparticles (NPs) containing Bletilla striatapolysaccharide (BSP) and omeprazole (OME) were investigated in the study for their therapeutic effect on gastric ulcers. Ethanol-induced gastric ulcers in rats (240 ± 30 g) were established. Our OME-BSP NPs were more stable than free OME in the acidic environment and can increase the absorption of OME in rat stomach, which was confirmed by in situ gastric absorption and distribution experiments. The extended blood circulation of OME-BSP NPs was also observed in rats with gastric ulcer. More importantly, OME-BSP NPs not only decreased the area of gastric ulcer and inhibited gastric acid secretion but also reversed gastric tissue damage and cell apoptosis, as revealed by HE and TUNEL staining. Subsequent SOD, MDA, PGE2, IL-6, and TNF-α tests further verified the superiority of OME-BSP NPs against rat gastric ulcer, which properly originated from superior antioxidant and anti-inflammatory effects. As a result, our OME-BSP NPs’ drug delivery system improved the stability and absorption of OME in the rat stomach and achieved targeted treatment of gastric ulcers.