This paper provides a comprehensive review of neurosyphilis, focusing on its pathogenesis, susceptibility, diagnosis, treatment, and prevention. *Treponema pallidum* can invade the central nervous system (CNS) at any stage of syphilis, leading to cognitive and behavioral abnormalities, limb paralysis, and potentially fatal outcomes. Early identification and prevention are crucial due to the lack of a gold standard for diagnosis and the high mortality rate associated with late-stage neurosyphilis. The review highlights the importance of cerebrospinal fluid examination in diagnosing neurosyphilis, although it lacks a definitive test. Intravenous aqueous crystalline penicillin G remains the recommended treatment, but the effectiveness of other antibiotics like doxycycline and ceftriaxone is also discussed. The paper emphasizes the need for novel public health strategies to manage the resurgence of neurosyphilis. Genetic factors, such as single-nucleotide polymorphisms (SNPs) in immune regulatory genes, are associated with increased susceptibility to neurosyphilis. Risk factors include male sex, advanced age, and high serological titers. The paper also discusses the role of HIV in increasing the risk of neurosyphilis and the importance of antiretroviral therapy in managing HIV-infected patients with syphilis. The review explores the mechanisms by which *T. pallidum* invades the CNS, including its ability to evade the immune system and interact with host cells. The biological characteristics of *T. pallidum*, such as its helical shape and flagellar motors, are described, along with its genetic makeup and strain typing methods. Prevention strategies, including preexposure prophylaxis (PrEP) and treatment as prevention (TasP), are discussed, along with the challenges and potential solutions for developing a syphilis vaccine. The paper concludes by emphasizing the need for further research and surveillance to improve the understanding and management of neurosyphilis.This paper provides a comprehensive review of neurosyphilis, focusing on its pathogenesis, susceptibility, diagnosis, treatment, and prevention. *Treponema pallidum* can invade the central nervous system (CNS) at any stage of syphilis, leading to cognitive and behavioral abnormalities, limb paralysis, and potentially fatal outcomes. Early identification and prevention are crucial due to the lack of a gold standard for diagnosis and the high mortality rate associated with late-stage neurosyphilis. The review highlights the importance of cerebrospinal fluid examination in diagnosing neurosyphilis, although it lacks a definitive test. Intravenous aqueous crystalline penicillin G remains the recommended treatment, but the effectiveness of other antibiotics like doxycycline and ceftriaxone is also discussed. The paper emphasizes the need for novel public health strategies to manage the resurgence of neurosyphilis. Genetic factors, such as single-nucleotide polymorphisms (SNPs) in immune regulatory genes, are associated with increased susceptibility to neurosyphilis. Risk factors include male sex, advanced age, and high serological titers. The paper also discusses the role of HIV in increasing the risk of neurosyphilis and the importance of antiretroviral therapy in managing HIV-infected patients with syphilis. The review explores the mechanisms by which *T. pallidum* invades the CNS, including its ability to evade the immune system and interact with host cells. The biological characteristics of *T. pallidum*, such as its helical shape and flagellar motors, are described, along with its genetic makeup and strain typing methods. Prevention strategies, including preexposure prophylaxis (PrEP) and treatment as prevention (TasP), are discussed, along with the challenges and potential solutions for developing a syphilis vaccine. The paper concludes by emphasizing the need for further research and surveillance to improve the understanding and management of neurosyphilis.