The use of bone implants and prostheses has contributed to a revolution in modern medicine; however, in the beginning, not much was asked from the implant and prosthetic materials per se. Therefore, the next game-changer in orthopedic research will come from new material designs which for instance can aid in prevention of implant-associated bone infections. Here, we describe the development of a new sol-gel coating technique that can deliver an efficient antimicrobial surface coating on orthopedic implants. Gentamicin was stocked in a novel nanocomposite xerogel made from silica and hyperbranched polyethyleneimine. The xerogel was anchored inside a porous surface made by coating of bone implants with titanium microspheres. Thereby, only the small water-soluble gentamicin molecules diffused in an aqueous environment, i.e., just after surgical insertion and leaving behind a titanium scaffold for osseointegration. The novel xerogel coating prevented development of severe Staphylococcus aureus induced osteomyelitis in a porcine model, which untreated, replicated the pathology seen in stage 3A on the Cierny–Mader classification system for osteomyelitis in adults.