Nearly half of the world’s population suffers from Helicobacter pylori (H. pylori) and gastric disorders. It is the most common pathogenic bacteria that cause gastritis, gastroduodenal ulcer disease, and gastric cancer. Because short residence period, a narrow absorption window in the upper small intestine results in poor bioavailability with standard dosage forms. In addition, combination therapies develop antibiotics, undesirable responses, and poor patient compliance. Therefore, these drawbacks may overcome by Gastro-retentive drug delivery systems (GRDDs). A site-specific drug delivery system comes into force for boosting the therapeutic oral bioavailability, prolonging the residence site, effective medication through a small absorption window of GIT, and stimulating local effect in the stomach and duodenum. This review highlighted anatomy and physiology of gastric barrier, various GRDDS approach, merits, demerits for improving drug delivery, and future perspectives. Finally, this review may benefit researchers and industrialists working in this field.