Skin infections are currently a worldwide emergency as antibiotic-resistant bacteria are spreading, leading to the ineffectiveness of most antibiotics and antibacterial strategies. Consequently, there is an urgency of developing and testing innovative antibacterial therapies. As traditional 2D cell culture and planktonic bacteria culture can be obsolete due to their incapability of resembling the complex infection environment, 3D in vitro skin models can be a powerful tool to test and validate therapies. In this article, a 3D in vitro epidermis-dermis skin model has been developed and biofabricated to be broadly available, reaching a balance between the simplicity and reproducibility of the model and its complexity in terms of wound, infection, and treatment response. The results are really promising, as the skin model developed a comprehensive physical barrier. To further investigate the skin model, controlled wounding, infection, and antibiotic treatments were performed. The results were remarkable: Not only was the unwounded epidermal barrier able to partially stop the bacterial proliferation, but the entire system reacted to both wound and infection in a complex and complete way. Extracellular matrix deposition and remodeling, inflammatory response, antimicrobial peptide production, and change in cellular behaviors, from epithelial to mesenchymal and from fibroblasts to myofibroblasts, were witnessed, with different extents depending on the bacterial strain. In addition, the inflammatory response to the antibiotic administration was opposite for the two bacterial infections, probably revealing the release of inflammatory endotoxins during Escherichia coli death. In conclusion, the presented 3D in vitro skin model has all the characteristics to be a future landmark as a platform for antibacterial strategy therapy testing.