Syphilis, a chronic systemic sexually transmitted disease, is caused by the bacterium Treponema pallidum ( T. pallidum ). Currently, syphilis remains a widespread infectious disease with significant disease burden in many countries. Despite the absence of identified penicillin-resistant strains, challenges in syphilis treatment persist due to penicillin allergies, supply issues, and the emergence of macrolide-resistant strains. Vaccines represent the most cost-effective strategy to prevent and control the syphilis epidemic. In light of the ongoing global coronavirus disease 2019 (COVID-19) pandemic, nucleic acid vaccines have gained prominence in the field of vaccine research and development, owing to their superior efficiency compared to traditional vaccines. This review summarizes the current state of the syphilis epidemic and the preliminary findings in T. pallidum nucleic acid vaccine research, discusses the challenges associated with the development of T. pallidum nucleic acid vaccines, and proposes strategies and measures for future T. pallidum vaccine development.