The emergence and reemergence of microbial infection demand an urgent response to develop effective biomaterials that prevent biofilm formation and associated bacterial infection. In this work, we have synthesized and characterized hybrid poly(N-hydroxyethylacrylamide) (polyHEAA)/salicylate (SA) hydrogels with integrated antifouling and antimicrobial capacities. The antifouling efficacy of polyHEAA hydrogels was examined via exposure to proteins, cells, and bacteria, while the antimicrobial activity of SA-treated polyHEAA hydrogels was investigated against both gram-negative Escherichia coli RP437 and gram-positive Staphylococcus epidermidis. The results showed that polyHEAA/SA hydrogels exhibited high surface resistance to protein adsorption, cell adhesion, and bacteria attachment. The polyHEAA hydrogels were also characterized by their water content and state of water, revealing a strong ability to contain and retain high nonfreezable water content. This work demonstrates that the hybrid polyHEAA/SA hydrogels can be engineered to possess both antifouling and antimicrobial properties, which can be used for different in vitro and in vivo applications against bacterial infection.