Antimicrobial-resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) have significantly restricted therapeutic alternatives for critical infections, consequently contributing to increase the severity and mortality of infectious illnesses that represent a significant global health challenge. Vaccination as a preventive measure can be crucial in substantially reducing bacterial infections and is potentially effective against antibiotic-resistant bacteria. This study shows the design of an epitope-based vaccine capable of neutralizing shared antigenic determinants present among the ESKAPE pathogens. The pangenome of the ESKAPE pathogens was analyzed to extract the core proteome. This approach facilitated reverse vaccinology analysis to identify antigenic proteins within this bacterial group. The study revealed similar structures in porins OmpA, OprD, and TolC, as well as the collagen-binding adhesins Acm and Cna. These proteins were then utilized to predict T-cell and B-cell epitopes, selecting those with their best physicochemical properties, antigenicity, non-allergenicity, and lack of toxicity. Additionally, epitopes located on the surface of the antigens and capable of coupling with HLA molecules were prioritized. In this computational approach, we engineered a construct incorporating the adjuvant RS09, a TLR4 agonist, and immunogenic epitopes connected by linkers. We assessed the stability of their interaction with pattern recognition receptors of the immune system through molecular docking and molecular dynamics simulations. The in silico immune simulation demonstrated that the vaccine could trigger humoral and cell-mediated immune responses. The resulting construct potentially represents an effective and safe vaccine candidate to prevent infections caused by the ESKAPE group.