Periprosthetic joint infection (PJI) is one of the formidable and recalcitrant complications after orthopedic surgery, and inhibiting biofilm formation on the implant surface is considered crucial to prophylaxis of PJI. However, it has recently been demonstrated that free-floating biofilm-like aggregates in the local body fluid and bacterial colonization on the implant and peri-implant tissues can coexist and are involved in the pathogenesis of PJI. An effective surface with both contact-killing and release-killing antimicrobial capabilities can potentially abate these concerns and minimize PJI caused by adherent/planktonic bacteria. Herein, Ag nanoparticles (NPs) are embedded in titania (TiO2) nanotubes by anodic oxidation and plasma immersion ion implantation (PIII) to form a contact-killing surface. Vancomycin is then incorporated into the nanotubes by vacuum extraction and lyophilization to produce the release-killing effect. A novel clinical PJI model system involving both in vitro and in vivo use of methicillin-resistant Staphylococcus aureus (MRSA) ST239 is established to systematically evaluate the antibacterial properties of the hybrid surface against planktonic and sessile bacteria. The vancomycin-loaded and Ag-implanted TiO2 nanotubular surface exhibits excellent antimicrobial and antibiofilm effects against planktonic/adherent bacteria without appreciable silver ion release. The fibroblasts/bacteria cocultures reveal that the surface can help fibroblasts to combat bacteria. We first utilize the nanoarchitecture of implant surface as a bridge between the inorganic bactericide (Ag NPs) and organic antibacterial agent (vancomycin) to achieve total victory in the battle of PJI. The combination of contact-killing and release-killing together with cell-assisting function also provides a novel and effective strategy to mitigate bacterial infection and biofilm formation on biomaterials and has large potential in orthopedic applications.