Although the eradication of Helicobacter pylori is critical for preventing gastric cancer, current therapies often overlook the restoration of the gastric microenvironment, leading to a prevalence of delayed tissue healing and dysbiosis. Consequently, many patients remain in a persistent pathological state despite successful H. pylori clearance, presenting a major bottleneck in clinical treatment. This review summarizes recent advancements in gastric-targeted drug delivery systems, illustrating the evolution from a singular antibacterial approach to an integrated sequential strategy encompassing clearance, repair, and homeostasis reconstruction. We examine smart gastro-retentive and nanodelivery systems designed to overcome physiological barriers, highlighting formulations that extend gastric residence time and maintain local drug concentrations above the Minimum Inhibitory Concentration for prolonged periods. Furthermore, we discuss spatiotemporally controllable biomaterials, such as Janus hydrogels and ROS-responsive carriers. These systems demonstrate distinct pH-dependent release kinetics and high stability in simulated gastric fluids, effectively preserving bioactive payloads to modulate the immune microenvironment. By facilitating the transition from pro-inflammatory to anti-inflammatory phenotypes, these biomaterials support epithelial regeneration. The review concludes with an analysis of postbiotics and the proposed holistic strategy, offering a promising therapeutic framework for mitigating the inflammation-to-cancer transition and promoting gastric health remodeling.