Neurosyphilis is a neurological infection caused by Treponema pallidum, which can invade the central nervous system (CNS) at any stage of syphilis. If T. pallidum is not cleared promptly, it can lead to neurosyphilis, characterized by cognitive and behavioral abnormalities, limb paralysis, and potentially fatal outcomes. Early identification and prevention of neurosyphilis are crucial. This review provides an updated narrative on the pathogenesis, susceptibility, diagnosis, treatment, and prevention of neurosyphilis. T. pallidum has a unique cellular structure, including a helical shape with a fragile dual-membrane structure and peptidoglycan layer, but lacks lipopolysaccharides. It can invade the CNS early in the disease, as demonstrated in rabbit, mouse, and human models. The presence of T. pallidum in the CNS suggests its ability to evade the immune system and actively invade the CNS, leading to sustained damage. Macrophages, particularly microglia in the CNS, act as the first line of immune defense. T. pallidum promotes microglial apoptosis and inhibits microglial migration, aiding in its evasion. Opsonic antibodies, such as TP0326 and TP0751, play a role in the clearance of T. pallidum. T. pallidum interacts with vascular endothelial cells, potentially contributing to its invasion of the CNS. It can adhere to human brain microvascular endothelial cells in vitro, altering the expression of tight junction proteins and influencing the permeability of the blood-brain barrier (BBB). The genome of T. pallidum comprises a circular chromosome with 1041 predicted open reading frames. Two major lineages, Nichols and SS14, are prevalent globally, with SS14 being more common. The SS14 lineage may be associated with neurosyphilis. Risk factors for neurosyphilis include male sex, advanced age, and high serological titers. HIV-negative patients with serum TRUST titers ≥1:16 are eight times more susceptible to developing neurosyphilis. HIV-positive individuals have additional risk factors, including high viral load and low CD4+ T cell counts. The synergism between HIV and T. pallidum is complex, and the characteristics of neurosyphilis can be confused with HIV infection. Predictive indicators for neurosyphilis include serum neurofilament light chain (NfL) and the neutrophil-to-lymphocyte ratio (NLR). These markers show promise as novel predictors for neurosyphilis. Diagnosis of neurosyphilis typically requires lumbar puncture, with CSF examination being essential. A positive CSF VDRL test is considered highly specific for neurosyphilis, while a nonreactive CSF FTA-ABS test is likely to exclude neurosyNeurosyphilis is a neurological infection caused by Treponema pallidum, which can invade the central nervous system (CNS) at any stage of syphilis. If T. pallidum is not cleared promptly, it can lead to neurosyphilis, characterized by cognitive and behavioral abnormalities, limb paralysis, and potentially fatal outcomes. Early identification and prevention of neurosyphilis are crucial. This review provides an updated narrative on the pathogenesis, susceptibility, diagnosis, treatment, and prevention of neurosyphilis. T. pallidum has a unique cellular structure, including a helical shape with a fragile dual-membrane structure and peptidoglycan layer, but lacks lipopolysaccharides. It can invade the CNS early in the disease, as demonstrated in rabbit, mouse, and human models. The presence of T. pallidum in the CNS suggests its ability to evade the immune system and actively invade the CNS, leading to sustained damage. Macrophages, particularly microglia in the CNS, act as the first line of immune defense. T. pallidum promotes microglial apoptosis and inhibits microglial migration, aiding in its evasion. Opsonic antibodies, such as TP0326 and TP0751, play a role in the clearance of T. pallidum. T. pallidum interacts with vascular endothelial cells, potentially contributing to its invasion of the CNS. It can adhere to human brain microvascular endothelial cells in vitro, altering the expression of tight junction proteins and influencing the permeability of the blood-brain barrier (BBB). The genome of T. pallidum comprises a circular chromosome with 1041 predicted open reading frames. Two major lineages, Nichols and SS14, are prevalent globally, with SS14 being more common. The SS14 lineage may be associated with neurosyphilis. Risk factors for neurosyphilis include male sex, advanced age, and high serological titers. HIV-negative patients with serum TRUST titers ≥1:16 are eight times more susceptible to developing neurosyphilis. HIV-positive individuals have additional risk factors, including high viral load and low CD4+ T cell counts. The synergism between HIV and T. pallidum is complex, and the characteristics of neurosyphilis can be confused with HIV infection. Predictive indicators for neurosyphilis include serum neurofilament light chain (NfL) and the neutrophil-to-lymphocyte ratio (NLR). These markers show promise as novel predictors for neurosyphilis. Diagnosis of neurosyphilis typically requires lumbar puncture, with CSF examination being essential. A positive CSF VDRL test is considered highly specific for neurosyphilis, while a nonreactive CSF FTA-ABS test is likely to exclude neurosy