Overcoming the multidrug-resistant (MDR) bacterial infection is a challenge and urgently needed in wound healing. Few wound dressings possess the capacity to treat MDR bacterial infections and enhance wound healing. Herein, we develop an elastomeric, photoluminescent, and antibacterial hybrid polypeptide-based nanofibrous matrix as a multifunctional platform to inhibit the MDR bacteria and enhance wound healing. The hybrid nanofibrous matrix was composed of poly(citrate)-ε-poly lysine (PCE) and poly caprolactone (PCL). The PCL–PCE hybrid nanofibrous matrix showed a biomimetic elastomeric behavior, robust antibacterial activity including killing MDR bacteria capacity, and excellent biocompatibility. PCL–PCE nanofibrous system can efficiently prevent the MDR bacteria-derived wound infection and significantly enhance the complete skin-thickness wound healing and skin regeneration in a mouse model. PCL–PCE hybrid nanofibrous matrix might become a competitive multifunctional dressing for bacteria-infected wound healing and skin regeneration.