A Y-shaped metallo-amphoteric monomer with cobaltocenium as the cation and sulfonyl as the anion was synthesized and used to prepare the corresponding metallo-polyampholyte hydrogel (PAH). The cobaltocenium in the amphoteric system and its Y-shape may introduce tunable supramolecular interactions, providing regulation of hydration properties and biomedical performance. Such metallo-PAH showed a higher water swelling ratio and comparable mechanical performance in comparison with its organic counterpart, polysulfobetaine methacrylate hydrogel (SBMA-PAH). Moreover, the metallo-PAH showed a good inhibitory effect against Gram-negative bacteria, Gram-positive bacteria, as well as corresponding drug-resistant bacteria. Interestingly, it was found that the metallo-PAH achieved as high as 95% antifouling property against different proteins in both short-term (2 h) and long-term (24 h) tests, which is much better than that of the SBMA-PAH (<
50%). It is believed that the concept of "metallo-polyampholyte" may expand the field of classical polyampholytes and related materials, thus opening up a new avenue to design powerful antifouling materials.