We report a case of calvarial lytic lesions in neurosyphilis with ocular involvement. A 42-year-old woman with a past medical history of polysubstance abuse presented with recent bilateral vision loss. CT revealed numerous calvarial lytic lesions and multiple myeloma was initially suspected. Syphilis screening with RPR and confirmative CSF studies were positive for active infection. The patient was treated with Penicillin G and demonstrated clinical improvement. The objective of this study was to provide insight into a rare manifestation of syphilis with osseous involvement and encourage further discourse into establishment of standards of care for syphilitic osteomyelitis. There exist no evidence-based guidelines regarding optimal treatment route and duration, role of bone biopsy, determination of therapeutic impact, and threshold for surgical intervention in the management of syphilitic osteomyelitis.