Syphilis is a chronic and multi-stage infectious disease caused by Treponema pallidum, which has a rapid spread, resistance to immune responses, and chronic infection. This review is a synthesis of animal evidence to study the pathogenesis, clinical synergies, diagnostic plans, treatment plans, and epidemiological implications of the disease. The use of animal models, especially rabbits, has been critical in understanding the interaction of the host and pathogen, development of lesions, and immunological reactions. This research indicates the relative performance of the traditional and reverse screening algorithm, which shows that reverse screening has a better sensitivity during both early and latent periods, whereas the traditional approach is useful in monitoring active infection. The development of molecular diagnostics, particularly PCR and immunoassays, has improved early diagnosis and evaluation of the disease, whereas penicillin remains the most effective treatment despite the emerging resistance issues in other treatments. Additionally, experimental epidemiological research adds to the knowledge on the dynamics and persistence of transmission. Nevertheless, animal model limitations and issues with vaccine development because of immune evasion remain a major problem. The review highlights the necessity of a better experimental model, combined diagnostic, and novel treatment and vaccine options to improve the management of the disease and future research outcomes.