Hypericum perforatum (HP) is a plant native to Asia and Europe. It has been documented to enclose medical effects against many disorders such as anxiety, depression and burns. This experiment was performed to evaluate the gastro-protective effect of Hypericum perforatum leaf extract in ethanol induced gastric ulcer in rats as compared to esomeprazole (the drug of choice for stomach ulcers). The mechanism of action was performed by Auto Dock Vina method. Ethanol ingestion up regulated the inflammatory reaction as demonstrated by rise of gastric proinflammatory TNF-α with a decline of IL-1β. On the other hand, the phytochemical screening of HP revealed the presence of alkaloids, flavonoids, tannins, phenols, steroids and saponins. The high dose of HP group shows mild injuries to the gastric mucosa which is comparable to the esomeprazole group, in contrast, severe damages are observed in the gastric mucosa of the ulcer control rats group. In silico results revealed that Amentoflavone and Quercitrin have highest affinity and very good interactions with H+/K+ ATPase α active site. This study showed that HP is nearly as effective as esomeprazole to prevent ethanol induced gastric ulcer the plant extract and it has more binding affinity than esomeprazole to gastric proton pumps.