Infective endocarditis (IE) has emerged as a public health problem due to changes in the etiologic spectrum and due to involvement of resistant bacterial strains with increased virulence. Developing potent vaccine is an important strategy to tackle IE. Complete genome sequences of eight selected pathogens of IE paved the way to design common T-cell driven subunit vaccines. Comparative genomics and subtractive genomic analysis were applied to identify adinosine tri phosphate (ATP)-binding cassette (ABC) transporter ATP-binding protein from Streptococcus mitis (reference organism) as common vaccine target. Reverse vaccinology technique was implemented using computational tools such as ProPred, SYFPEITHI, and Immune epitope database. Twenty-one T-cell epitopes were predicted from ABC transporter ATP-binding protein. Multiple sequence alignment of ABC transporter ATP-binding protein from eight selected IE pathogens was performed to identify six conserved T-cell epitopes. The six selected T-cell epitopes were further evaluated at structure level for HLA-DRB binding through homology modeling and molecular docking analysis using Maestro v9.2. The proposed six T-cell epitopes showed better binding affinity with the selected HLA-DRB alleles. Subsequently, the docking complexes of T-cell epitope and HLA-DRBs were ranked based on XP Gscore. The T-cell epitope (208-LNYITPDVV-216)-HLA-DRB1(∗)0101 (1T5 W) complex having the best XP Gscore (-13.25 kcal/mol) was assessed for conformational stability and interaction stability through molecular dynamic simulation for 10 ns using Desmond v3.2. The simulation results revealed that the HLA-DRB-epitope complex was stable throughout the simulation time. Thus, the epitope would be ideal candidate for T-cell driven subunit vaccine design against infective endocarditis.