The use of implants or indwelling medical devices has greatly enhanced the quality and efficacy of health care. However, foreign-body reactions (FBRs) and infections can lead to potential failure or removal of the devices, or increased morbidity and mortality of patients. Herein, we develop a silver nanoparticle (AgNP) loaded poly(hydroxyethyl methacrylate) hydrogel with spherical, interconnected 40 μm pores. The resulting hydrogels displayed good antibacterial properties regarding both gram positive bacteria (Staphylococcus aureus) and gram negative bacteria (Escherichia coli (E. coli)) in vitro and were highly efficient at inhibiting bacterial cell growth. Moreover, they exhibited an in vivo resistance to FBRs by reducing the immune responses, and completely prevented the formation of collagen capsules. Finally, in vivo studies of the E. coli infected mouse model demonstrated that the AgNP loaded porous hydrogels were highly efficient at resisting the bacterial FBRs and infections, while they promoted cell mitigation and infiltration. Findings from this work suggest that AgNP loaded porous hydrogels hold promise in various biomedical applications including in the new generation of implantable biomedical devices and tissue engineering scaffolds.