Silver nanoparticles (Ag NPs) have unique properties and display an important role in bioactivities such as antimicrobial, antiviral, antifungal, and anticancer. Stable Ag NPs were prepared by reaction of silver nitrate solution with extract of Melissa and characterized by UV-Vis spectroscopy, AFM, SEM, XRD, and Zeta potential. The resulted Ag NPs have a size range between 20 and 35 nm. The current study aims to evaluate the gastroprotective effect of Ag NPs against ethanol-induced gastric ulcers in rats. Thirty rats were randomly divided into five groups. The experimental groups were fed 175 and 350 ppm/p.o of Ag NPs orally. Ag NPs improved the adversative influence of ethanol-induced stomach damage as confirmed by declining ulcer index and raised the percentage of ulcer prevention. Significantly reduced ethanol-induced gastric lesions were evidenced by increased mucus secretion and pH of stomach content, decreased ulcer area, nonappearance of edema, and leucocyte penetration of the subcutaneous layer. In gastric homogenate, Ag NPs displayed a substantial upsurge in superoxide dismutase (SOD), catalase (CAT) activities, and significantly reduced malondialdehyde (MDA) levels., Ag NPs increased the intensity of periodic acid Schiff stained (PAS) and produced over-regulation of HSP-70 and down-regulation of Bax proteins. Ag NPs confirmed gastro-protection which might be attributed to its antioxidant effect, increased mucus secretion, increased SOD, and CAT, reduced MDA level, over-regulation of HSP-70 protein, and down-regulation of Bax protein.