Uncontrolled bleeding and infections, particularly from drug-resistant bacteria like Methicillin-Resistant Staphylococcus aureus (MRSA), pose significant challenges in clinical wound management, delaying healing, increasing patient discomfort, and elevating healthcare costs. This study introduces a novel reactive oxygen species (ROS)-responsive collagen-based hemostatic sponge designed to enhance wound healing and minimize blood loss, especially in MRSA-infected wounds. By chemically modifying the carboxyl groups of collagen with amino-rich oligomers, the primary amino content was increased, enhancing drug loading capacity-particularly for vancomycin-while also improving the sponge's mechanical properties, hemostatic performance, and biological stability. The ROS-responsive covalent bonding of vancomycin facilitated controlled vancomycin release in response to ROS, offering superior antibacterial efficacy and specifically targeting MRSA more effectively than conventional non-ROS-responsive approaches. In MRSA-infected full-thickness skin repair models, the ROS-responsive vancomycin-loaded sponge significantly enhanced wound healing and skin regeneration compared to both the physical adsorption group and the non-ROS-responsive release group. These results underscore the potential of the ROS-responsive collagen composite as an advanced hemostatic material with enhanced antibacterial capabilities, providing rapid hemostasis and improved healing outcomes for complex or infected wounds.