Acute and chronic bone infections, especially those caused by methicillin-resistantStaphylococcus aureus(MRSA), remains a major complication and therapeutic challenge. It is documented that local administration of vancomycin offers better results than the usual routes of administration (e.g., intravenous) when ischemic areas are present. In this work, we evaluate the antimicrobial efficacy againstS. aureusandS. epidermidisof a novel hybrid 3D-printed scaffold based on polycaprolactone (PCL) and a chitosan (CS) hydrogel loaded with different vancomycin (Van) concentrations (1, 5, 10, 20%). Two cold plasma treatments were used to improve the adhesion of CS hydrogels to the PCL scaffolds by decreasing PCL hydrophobicity. Vancomycin release was measured by means of HPLC, and the biological response ofah-BM-MSCs growing in the presence of the scaffolds was evaluated in terms of cytotoxicity, proliferation, and osteogenic differentiation. The PCL/CS/Van scaffolds tested were found to be biocompatible, bioactive, and bactericide, as demonstrated by no cytotoxicity (LDH activity) or functional alteration (ALP activity, alizarin red staining) of the cultured cells and by bacterial inhibition. Our results suggest that the scaffolds developed would be excellent candidates for use in a wide range of biomedical fields such as drug delivery systems or tissue engineering applications.