Background <p>Syphilis is a multifaceted disease caused by <i>Treponema pallidum.</i> It has re-emerged as a public health concern and represents a potentially treatable cause of cerebrovascular disease. Neurosyphilis (NS) can involve the central nervous system at any stage of infection, with meningovascular syphilis leading to ischemic or, less frequently, hemorrhagic stroke. Diagnosis remains challenging due to heterogeneous clinical presentations and challenging serological diagnostics.</p> Methods <p>We report a case of ischemic stroke as the first manifestation of syphilis and performed a systematic review of the literature on syphilis-associated stroke. A structured search of PubMed, the COCHRANE Library, and secondary sources was conducted for studies published from 1972 onward.</p> Results <p>The reported case describes a 44-year-old HIV-negative man presenting with ischemic stroke due to presumed small-vessel meningovascular syphilis, supported by CSF pleocytosis and positive treponemal serology in serum and CSF. The patient improved substantially following ceftriaxone therapy. The systematic review identified 98 relevant publications, including 73 individual cases and 36 cohort studies. Stroke frequently led to the initial diagnosis of syphilis and predominantly affected younger male patients. Ischemic stroke was the most common presentation, mainly due to large-vessel disease. Penicillin was the most frequently used therapy, with ceftriaxone as an effective alternative.</p> Discussion <p>Syphilis is an important and underrecognized risk factor for stroke, particularly in younger patients. NS should be considered in cases of cryptogenic stroke, and standardized diagnostic and therapeutic approaches are needed to improve recognition and outcomes. Few data on the specific stroke treatment in syphilis exist.</p>