Despite significant advancements in material science, surgical site infection (SSI) rates remain high and prevention is key. This study aimed to demonstrate the in vivo safety and antibacterial efficacy of titanium implants treated with a novel broad-spectrum biocidal compound (DBG21) against methicillin-resistant Staphylococcus aureus (MRSA). Titanium (Ti) discs were covalently bound with DBG21. Untreated Ti discs were used as controls. All discs were implanted either untreated for 44 control mice or DBG21-treated for 44 treated mice. After implantation, 1 × 10⁷ colony forming units (CFU) of MRSA were injected into the operating site. Mice were killed at 7 and 14 days to determine the number of adherent bacteria (biofilm) on implants and in the peri-implant surrounding tissues. Systemic and local toxicity were assessed. At both 7 and 14 days, DBG21-treated implants yielded a significant decrease in MRSA biofilm (3.6 median log10 CFU [99.97%] reduction [p < 0.001] and 1.9 median log₁₀ CFU [98.7%] reduction [p = 0.037], respectively) and peri-implant surrounding tissues (2.7 median log₁₀ CFU/g [99.8%] reduction [p < 0.001] and 5.6 median log₁₀ CFU/g [99.9997%] reduction [p < 0.001], respectively). There were no significant differences between control and treated mice in terms of systemic and local toxicity. DBG-21 demonstrated a significant decrease in the number of biofilm bacteria without associated toxicity in a small animal implant model of SSI. Preventing biofilm formation has been recognized as a key element of preventing implant-related infections.