This work aimed to use hot-melt extrusion (HME) and dual fused deposition modeling (FDM) 3D printing technology to develop a novel intragastric floating and sustained-release drug delivery system. The intragastric floating and sustained-release tablet was engineered by employing hydroxypropyl methylcellulose (Affinisol HPMC HME 15LV) for a drug-loaded core and polylactic acid (PLA) for an insoluble shell with an air chamber. Filaments for the drug-loaded core were compounded using a single-screw hot melt extruder. 3DMAX software was utilized to design a core with a complementary shell which consisted of a hollow chamber at the top and a drug-release window with different sizes (radius in 1.5, 2.5, 3, 3.5, 4.5 mm) at the bottom. Pharmaceutical characterization, solid dispersion evaluation, and drug release behavior were studied. The model drug in all formulations kept stable, and part of the drug in the extruded filaments and 3D printed tablets became amorphous. The introduction of an air chamber reduced the tablet density to below 0.9 g/cm and the 3D printed tablets floated immediately and continuously during the drug release process. The presence of the insoluble shell greatly prolonged the drug release time, and the drug release rate was positively correlated with the area of the release window. In addition, compared with shellless tablets, the 3D printed tablets with air chambers (radius in 4.5 mm) showed closer zero-order drug release for 24 h and released drug by diffusion-erosion combined mechanism. The developed intragastric floating and sustained-release tablets with air chambers could be applied to various drugs and provided a new way for the development of personalized drug delivery systems.