Syphilis, caused by the spirochete bacterium Treponema pallidum, has posed a global public health challenge since the fifteenth century. This chapter provides a comprehensive exploration of the multifaceted nature of syphilis, its historical background, and the emerging threat of antimicrobial resistance (AMR) in its management. A mother infected with syphilis during pregnancy can transmit the disease to her unborn child, and this sexually transmitted infection sy can progress through various stages, each presenting different symptoms and characteristics. The initial focus is on the escalating concern of resistance in syphilis, as it compromises the effectiveness of conventional treatment strategies, particularly the shortage of Benzathine penicillin G reported in some regions. Certain populations, including pregnant women, individuals with HIV, and men who engage in intercourse with males, are particularly at risk due to the increasing prevalence of bacteria that are resistant to penicillin and its replacements, tetracycline and macrolides. To overcome syphilis resistance, a combination of therapies is one of the most effective strategies. While a single antibiotic is frequently used for the duration of syphilis therapy, mixing several antimicrobial medications can improve treatment efficacy and reduce the likelihood that resistance will develop. The synergistic effects of antibiotic combinations such azithromycin, doxycycline, and benzathine penicillin have been researched. This chapter aims to raise awareness about the urgent public health crisis posed by AMR in syphilis. Examining the causes, background, along with mechanisms of syphilis highlights the need for a worldwide strategy to tackle the growing issue of antibiotic resistance. In order to create effective strategies to stop the dissemination of resistant strains, give appropriate care, and lessen the public health burden of syphilis, it is essential to understand the many aspects of antimicrobial resistance (AMR) in syphilis.