Background: The control of gastric acid secretion is an orchestration of neuronal and hormonal signaling that regulates the secretion of hydrochloric acid. Ghrelin is one of the gut derived peptide hormones. It was reported to play a role in modulation of gastric secretory function, which is still controversial. The present study was designed to investigate the possible effect of ghrelin on the basal gastric acid secretion. Also, to study if this action is mediated through nitric oxide or prostaglandins. In addition, the effect of ghrelin on aspirin induced gastric ulcers was investigated. Methods: 56 adult male albino rats were divided into 2 modules (n=8/group): Module A: basal gastric acid secretion groups; control group, ghrelin treated group, ghrelin + L-NAME treated group, ghrelin + Indomethacin treated group and ghrelin + L-NAME+ Indomethacin treated group ,for these groups pyloric ligation was done, and after 3 hours the rats were sacrificed, basal gastric secretion volume and acid secretion (free and total) were measured, then the gastric tissue was used for assessment of eNOS enzyme activity, COX-I enzyme activity, gastrin gene expression, and proton pump gene expression. Module B: ulcer formation groups; ulcer induced group and ulcer induced ghrelin treated group. Rats were sacrificed after 2 hours, stomachs were removed and ulcer index was measured for each stomach. Results: According to the results of module A, ghrelin was found to increase basal gastric acid secretion, enzymatic level of e-NOS and COX-1 enzymes in comparison to the control level, indicating a possible participation in the given ghrelin effect. This possibility was strengthened by the use of antagonists for both enzymes separately and then simultaneously. It was reported that blockage of e-NOS by L-NAME significantly decreased the ghrelin effect on gastric acid secretion, which was the same result of antagonizing COX enzyme by indomethacin. Simultaneous blockage of both enzymes using the 2 antagonists together returned gastric acid secretion parameters back to the level of the control. Gastrin gene expression and proton pump gene expression were both elevated under the effect of exogenous ghrelin. Blockage of NOS and COX partially abolished the effect of ghrelin on both expressions ,but it was still significantly high in comparison to the control levels In module B ;ghrelin treated group had a significantly lower ulcer index in comparison to the aspirin induced ulcer group in both circular and linear indices. This added an evidence that ghrelin can act as a gastroprotective peptide. Conclusions: Intravenous injected ghrelin has a stimulatory effect on basal gastric acid secretion. The mechanism of this stimulation was proved to involve mainly NO synthesis, and it’s also partially dependent on COX-1 derived PGs, ghrelin action on gastric acid secretion involves induction of gastrin and proton pump genes expression in the gastric tissue, which was also proved to be dependent on NO and PG synthesis, but these are not the only mechanisms by which ghrelin affects the expression of gastrin and proton pump, a finding that needs further study to investigate other possible mechanisms for this effect