Zwitterionic polymers such as poly(sulfobetaines) and polyether polymers such as poly(ethylene glycol) (PEG) have both been reported as effective antifouling materials for various biomedical applications based on their high-water-binding capacities through hydrogen bonding (PEG) or ion-dipole interactions (zwitterionic polymers). Herein, to assess whether synergistic antifouling properties can be achieved when poly(sulfobetaine) and PEG moieties are combined into a single polymer, linear copolymers were fabricated by the chain transfer radical copolymerization of [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (DMAPS) and oligo(ethylene glycol) methyl ether methacrylate (OEGMA) together with a functional comonomer that introduced an aldehyde or hydrazide functional group to enable in situ gelation via hydrazone cross-linking. In general, hydrogels prepared with more OEGMA showed longer gelation times, increased protein uptake (because of their higher degree of swelling), and faster plasma clotting times. However, hydrogels prepared with hydrazide precursor polymers with a 90:10 molar ratio of DMAPS:OEGMA exhibited significantly lower protein adsorption as well as lower peak thrombin upon exposure to blood plasma compared to either single-component gel. This result was rationalized by molecular dynamics simulations indicating that the 90:10 DMAPS:OEGMA ratio facilitates enhanced total hydration, a more dynamic hydration sphere, and suppressed zwitterion fusion interactions. Overall, the results suggest a potential benefit of introducing multiple types of water-binding mechanisms into a single antifouling biomaterial.