Nonspecific protein adsorption impedes the sustainability of materials in biologically related applications. Such adsorption activates the immune system by quick identification of allogeneic materials and triggers a rejection, resulting in the rapid failure of implant materials and drugs. Antifouling materials have been rapidly developed in the past 20 years, from natural polysaccharides (such as dextran) to synthetic polymers (such as polyethylene glycol, PEG). However, recent studies have shown that traditional antifouling materials, including PEG, still fail to overcome the challenges of a complex human environment. Zwitterionic materials are a class of materials that contain both cationic and anionic groups, with their overall charge being neutral. Compared with PEG materials, zwitterionic materials have much stronger hydration, which is considered the most important factor for antifouling. Among zwitterionic materials, zwitterionic hydrogels have excellent structural stability and controllable regulation capabilities for various biomedical scenarios. Here, we first describe the mechanism and structure of zwitterionic materials. Following the preparation and property of zwitterionic hydrogels, recent advances in zwitterionic hydrogels in various biomedical applications are reviewed.