<p>Herpes Simplex Virus 2 (HSV-2) infection is a global concern, affecting around 500 million individuals worldwide and being the leading cause of genital ulcers. Although several HSV vaccine candidates have been tested in humans, as of right now, neither HSV type has a licenced vaccination available. This study utilized reverse vaccinology to conduct an extensive analysis of the entire genome of HSV-2 where glycoprotein-D was chosen for T-cell epitope predictions. Through an immunoinformatic approach, we identified 2 novel CD8 + and 8 CD4 + T-cell epitopes overlapped within conformational B-cell epitopes, which hold promise as potent vaccine candidates. These epitopes were highly immunogenic and non-toxic, and also showed significant population coverage all over the world. Notably, the predicted epitopes demonstrated cross-reactivity with HSV-1, with the majority exhibiting over 80% conservation within glycoprotein-D. In addition, the designed vaccines’ physicochemical properties revealed that these vaccines are non-toxic and non-allergenic, exhibited highly antigenic properties and had the potential to interact with immune receptors effectively. Furthermore, molecular docking studies with human immune receptors, specifically TLR2, demonstrated robust interactions, supported by molecular dynamics simulations indicating stable binding and dynamics. Finally, via codon optimization and in silico cloning, the vaccine candidates were successfully expressed in <i>Escherichia coli</i>, demonstrating feasibility for large-scale production. Computational immune response modelling following varied dosages suggested that the immunogenic constructs could elicit significant immune responses. In conclusion, this study presents promising vaccine candidates against HSV-2, utilizing a rational design approach. However, experimental validation is necessary before advancing to clinical trials.</p>