Submucosal elevation, the process of instilling material in the submucosal space for separation of the surface mucosa and deeper muscularis layer, is a significant aspect of the endoscopic mucosal resection of large lesions performed to facilitate lesion removal and maximize safety. Submucosal injection, when applied, has historically been performed with normal saline, though this is limited by its rapid dissipation; solutions ideally need to be easily injectable, biocompatible, and provide a long-lasting submucosal cushion with a desirable height. Here, reported is a new set of materials, endoscopically injectable shear-thinning hydrogels, meeting these requirements because of their biocompatible components and ability to form a solid hydrogel upon injection. These findings are supported by evaluation in a large animal model and ultimately demonstrate the potential of these shear-thinning hydrogels to serve as efficient submucosal injection fluids for cushion development. Given these unique characteristics, their broad application in mucosal resection techniques is anticipated.