Topical antimicrobial treatments are often ineffective on recalcitrant and resistant skin infections. This necessitates the design of antimicrobials that are less susceptible to resistance mechanisms, as well as the development of appropriate delivery systems. These two issues represent a great challenge for researchers in pharmaceutical and drug discovery fields. Here, we defined the therapeutic properties of a novel peptidomimetic inspired by an antimicrobial sequence encrypted in human apolipoprotein B. The peptidomimetic was found to exhibit antimicrobial and anti-biofilm properties at concentration values ranging from 2.5 to 20 µmol L−1, to be biocompatible toward human skin cell lines, and to protect human keratinocytes from bacterial infections being able to induce a reduction of bacterial units by two or even four orders of magnitude with respect to untreated samples. Based on these promising results, a hyaluronic-acid-based hydrogel was devised to encapsulate and to specifically deliver the selected antimicrobial agent to the site of infection. The developed hydrogel-based system represents a promising, effective therapeutic option by combining the mechanical properties of the hyaluronic acid polymer with the anti-infective activity of the antimicrobial peptidomimetic, thus opening novel perspectives in the treatment of skin infections.