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The main antimicrobial resistance (AMR) nosocomial strains (ESKAPE pathogens such as <i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Enterobacter</i> spp.) are the most widespread bacteria in cutaneous infections. In this work we report the synthesis, in silico skin permeability prediction, antimicrobial, antibiofilm, and wound healing properties of novel cinnamic acid-based antimicrobials (<b>DM1–11</b>) as novel antibacterial drugs for the treatment of ESKAPE-related skin infections. Antimicrobial and wound healing scratch assays were performed to evaluate the antibacterial properties of <b>DM1–11</b>. In silico skin permeability capabilities of <b>DM1–11</b> were evaluated using Swiss-ADME online database. Cytotoxicity assays were performed on keratinocytes and fibroblasts. <b>DM2</b>, bearing a catechol group on the aromatic ring of the cinnamic portion of the molecule, possesses a significant antibacterial activity against <i>S. aureus</i> (MIC range 16–64 mg/L) and contrasts the biofilm-mediated <i>S. epidermidis</i> infection at low concentrations. Wound healing assays showed that wound closure in 48 h was observed in <b>DM2</b>-treated keratinocytes with a better healing pattern at all the used concentrations (0.1, 1.0, and 10 µM). A potential good skin permeation for <b>DM2</b>, that could guarantee its effectiveness at the target site, was also observed. Cytotoxicity studies revealed that <b>DM2</b> may be a safe compound for topical use. Taking together all these data confirm that <b>DM2</b> could represent a safe wound-healing topical agent for the treatment of skin wound infections caused by two of main Gram-positive bacteria belonging to ESKAPE microorganisms.