To examine the protective effect and mechanism of the original extract of Dendrobium officinale (DE) on gastric lesions caused by aspirin (ASA) facilitate the development of traditional Chinese medicine products. In this study, a gastric lesions rat model was established, and then the rats were treated with DE for 5 days. We found that ASA-induced gastric mucosal detachment and hemorrhagic lesions in rats improved after DE supplementation. Meanwhile, effectively inhibits the secretion of inflammatory mediators (IL-6, IL-1β, TNF-α, MPO, COX-2) and upregulates the activity of antioxidant core components (T-SOD, GSH-Px) and defense factors (TFFs, EGF, EGFR) in gastric tissues. It was further found that DE exerted a defensive effect on the gastric mucosa in association with NF-κB/Nrf-2/HO-1 signaling. In conclusion, DE protects the gastric mucosa from oxidative stress, improves its defenses, as well as being a potential gastric mucosal nutrient in the future, preventing ASA-induced gastric lesions.