Surgical site infections (SSIs) are among the most frequent healthcare-associated infections, resulting in high morbidity, mortality, and cost. While correct hygiene measures and prophylactic antibiotics are effective in preventing SSIs, even in modern healthcare settings where recommended guidelines are strictly followed, SSIs persist as a considerable problem that has proven hard to solve. Surgical procedures involving the implantation of foreign bodies are particularly problematic due to the ability of microorganisms to adhere to and colonize the implanted material and form resilient biofilms. In these cases, SSIs may develop even months after implantation and can be difficult to treat once established. Locally applied antibiotics or specifically engineered implant materials with built-in antibiotic-release properties may prevent these complications and, ultimately, require fewer antibiotics compared to those that are systemically administered. In this study, we demonstrated an antimicrobial material concept with intended use in artificial vascular grafts. The material is a silicone–hydrogel interpenetrating polymer network developed earlier for drug-release catheters. In this study, we designed the material for permanent implantation and tested the drug-loading and drug-release properties of the material to prevent the growth of a typical causative pathogen of SSIs, Staphylococcus aureus. The novelty of this study is demonstrated through the antimicrobial properties of the material in vitro after loading it with an advantageous combination, minocycline and rifampicin, which subsequently showed superiority over the state-of-the-art (Propaten) artificial graft material in a large-animal study, using a novel porcine tissue-implantation model.