Staphylococcus epidermidis has emerged as a major contributor of nosocomial infections across the world. With the increased rate of emerging resistant and previously undefined infectious diseases, there is a growing need to develop a novel vaccine possessing required immunogenic properties. The adopted reverse vaccinology approach identified “IMPNQILTI” of LysM domain protein, “YSYTYTIDA” of staphylococcal secretory antigen SsaA, and “YNYDANTGQ” neutral metalloproteinaseas potential peptides for vaccine design. The 9-mer epitope of target proteins is antigenic, virulent, surface-exposed, non-allergenic, and conserved across various strains of S. epidermidis. Protein-protein interactions study indicated the involvement of target proteins in major biological pathways for S. epidermidis pathogenesis. Protein-peptide docking was performed, and population coverage analysis showed significant interactions of T-cell epitopes with the HLA-binding molecules while covering 90.58% of the world's population. Further, a multi-epitope vaccine of 177 amino acids long was constructed. Docking with Toll-like receptor (TLR-2) molecule confirmed the effective interaction of the vaccine with the receptor. The vaccine efficiency in generating an effective immune response in the host was evaluated by immune simulation. Finally, in silico cloning confirmed that the constructed vaccine can be efficiently expressed in E. coli. However, the designed vaccine needs experimental validation to determine the effectiveness and immunogenicity profile, which will ensure an active immunity against S. epidermidis.