Syphilis, a global healthcare burden, is a sexually transmitted infection caused by the spirochete Treponema pallidum, a spiral-shaped, Gram-negative obligate human pathogen. Despite its easy identification and treatability, the disease affects over 50 million people worldwide, with 8 million new cases in the 15–49 age group annually, as per the WHO 2024 report. If left untreated, syphilis progresses through its primary, secondary, latent, and tertiary stages, causing severe complications like neurosyphilis, congenital syphilis, and organ damage. The first-line treatment, penicillin, faces challenges, including logistical issues, shortages, allergic reactions, and patient non-compliance. Secondary treatment options are sparse, and there are reported cases of T. pallidum strains resistant to those antibiotics. The absence of an effective vaccine for syphilis has led to efforts to control its spread through sexual education, condom usage, and post-exposure prophylaxis with doxycycline, which raises concerns about antimicrobial resistance (AMR). The continued reliance on penicillin and the increasing rates of doxycycline post-exposure prophylaxis (DoxyPEP) use have both contributed to concerns about AMR development. Recent works pointing to emerging antibiotic resistance and treatment failures highlight the urgent need for new antibiotics to manage syphilis effectively and reduce dependency on penicillin. This review has focused on the shortcomings and limitations of penicillin treatment, recently identified antimicrobial-resistant strains of T. pallidum, and case studies where its application failed to treat the disease adequately.