Collagen VI is a ubiquitous extracellular matrix component that forms extensive microfibrillar networks in most connective tissues. In 2012 we discovered that the collagen VI von Willebrand factor type A-like (VWA) domains of the alpha-3 chain exhibit a broad-spectrum antimicrobial activity against Gram-positive and Gram- negative bacteria in skin infections in vivo. In silico sequence and structural analysis of VWA domains revealed that the alpha-3 chain contains cationic and amphipathic peptide sequence motifs. In vitro and in vivo studies show that these peptides exhibited significant antibacterial activity against “normal” and multidrug-resistant microorganisms through physical membrane disruption. Further in vitro and in vivo studies demonstrated that the same collagen VI-derived peptides actively promote rapid wound closure and wound healing. Taken together, during naturally evolved mechanisms, collagen VI is present in skin wounds where it promotes wound healing and efficiently protects the wound from bacterial infections. Our findings paved the way to develop a novel, highly bioactive wound dressing consisting of a combination of a natural collagen I matrix and collagen VI peptides.