<p>Poor adherence to oral drug regimens adversely affects treatment outcomes and contributes substantially to preventable healthcare costs, underscoring the need for long-acting drug delivery systems that sustain therapeutic levels over extended periods. To address this, we developed an origami-inspired, oral drug delivery dosage form capable of prolonged residence in the gastric cavity. This system achieves ease of administration and extended gastric residency through geometric design and shape optimization, allowing the dosage form to fold inside a standard ingestible capsule. Upon the capsule’s dissolution in the stomach, the dosage form rapidly transforms into its deployed configuration. Our formulation and manufacturing techniques enable the development of a long-acting dosage form with up to 40% weight loading capacity of sample drugs, such as moxifloxacin. The high surface-area-to-volume ratio of the origami design enables approximately linear release kinetics over the observed time window of candidate drugs. We incorporated pH-sensitive elements that dissolve in the neutral portions of the GI tract into the dosage form to promote its dissociation and safe transit in the intestine. In vitro and in vivo studies using swine models demonstrated extended gastric residency of up to three weeks (with a minimum of one week) and an approximately constant release rate for three days. Endoscopic and radiographic evaluations of the animal models confirmed that the dosage forms safely pass through the intestine without causing gastrointestinal obstruction or injury.</p>