Novel biomineralized hydrogels composed of hyaluronic acid (HA) and vinyl phosphonic acid (VPAc) were designed with the aim of developing a biomimetic hydrogel system to improve bone regeneration by local delivery of a protein drug including bone morphogenetic proteins. We synthesized crosslinked hydrogels composed of methacrylated HA and poly(VPAc) [P(VPAc)], which serves as a binding site for calcium ions during the mineralization process. The HA/P(VPAc) hydrogels were biomineralized by a urea-mediation method to create functional polymer hydrogels that can deliver the protein drug and mimic the bone extracellular matrix. The water content of the hydrogels was influenced by the HA/P(VPAc) composition, crosslinking density, biomineralization, and ionic strength of the swelling media. All HA/P(VPAc) hydrogels maintained more than 84% water content. Enzymatic degradation of HA/P(VPAc) hydrogels was dependent on the concentration of hyaluronidase and the crosslinking density of the polymer network within the hydrogel. In addition, the release behavior of bovine serum albumin from the HA/PVPAc hydrogels was mainly influenced by the drug loading content, water content, and biomineralization of the hydrogels. In a cytotoxicity study, the HA/P(VPAc) and biomineralized HA/P(VPAc) hydrogels did not significantly affect cell viability. These results suggest that biomineralized HA/P(VPAc) hydrogels can be tailored to create a biomimetic hydrogel system that promotes bone tissue repair and regeneration by local delivery of protein drugs. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 41194.