Endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (ESR) are used to eliminate tiny, flat lesions in the gastrointestinal tract (GIT). A substantial submucosal cushion is required for effective dissection. Commonly used saline and hypertonic dextrose injections disperse quickly and do not offer significant elevation, whereas polymers such as gelatin and alginate are challenging to inject. In this study, a novel amphiphilic polyglycerol stearate-based hydrogel (PGSH) platform is demonstrated which could be administered via an endoscopic catheter to help create a stable submucosal elevation. PGSH is easy to inject across different needle gauges, shear-thinning, and forms a long-lasting submucosal cushion during ESD. This hydrogel can encapsulate hydrophilic drugs such as streptomycin, allowing controlled enzymatic and nonenzymatic release. Ex-vivo experiments on goat's GIT demonstrate that PGSH is smoothly injectable without clogging the catheter's needle, achieving the necessary submucosal elevation. Furthermore, ex-vivo blood studies demonstrate immediate clotting behavior while maintaining hemocompatibility. In-vivo, investigations in mice show that the hydrogel forms a biocompatible cushion of suitable height with a nontoxic organ profile that does not overexpress inflammatory cytokines. ESD studies in the porcine model suggest that PGSH has the potential to significantly improve treatment outcomes in the early endoscopic removal of gastrointestinal polyps.