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This system combines the angiogenic and immunomodulatory peptide LLKKK18 (LL18) and vancomycin hydrochloride (VH), loaded into an injectable oxidized dextrin (ODEX)\u2010based hydrogel (HG). In vitro cytotoxicity was analyzed in MC3T3\u2010E1 pre\u2010osteoblasts and erythrocytes. The kinetics of LL18 release was studied. Antimicrobial activity was assessed in vitro against a clinical Methicillin\u2010Resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA) strain. A rat model of acute OM was developed by direct inoculation into a tibia defect, concomitantly with the implantation of the drug\u2010loaded HG. The local bioburden was quantified and damage in surrounding tissues was examined histologically. In vitro<jats:italic>,<\/jats:italic> ODEX\u2010based HG displayed a safe hemolytic profile. Half of LL18 (53%) is released during the swelling phase at physiological pH, then being gradually released until complete HG degradation. LL18\u2010loaded HG at 300\u2009\u03bcM was the most effective peptide formulation in decreasing in vivo infection among concentrations ranging from 86 to 429\u2009\u03bcM. The histopathological scores observed in vivo varied with the LL18 concentration in a dose\u2010dependent manner. VH at 28\u2009mM completely eradicated bacteria, although with substantial tissue injury. We have found that sub\u2010millimolar doses of VH combined with LL18 at 300\u2009\u03bcM may suffice to eradicate the infection, with reduced tissue damage. 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