Although the incidence of syphilis reached a historic low in 2000, the number of incident cases has since increased in men and women across the USA. In 2019, men who have sex with men (MSM) accounted for 57% of all primary and secondary (P&S) syphilis cases, and about half of MSM with P&S syphilis are living with human immunodeficiency virus (HIV) infection. Days after infection, Treponema pallidum disseminates and invades tissues distant from the site of inoculation. Once the spirochete disseminates, the host develops an inflammatory response; diagnosis requires a high level of suspicion since syphilis may affect the skin, musculoskeletal, cardiovascular, and central nervous systems. We report a 61-year-old man with virally suppressed HIV infection who presented with polyarthralgia, chest pain, and weight loss, diagnosed with secondary syphilis, manifesting with ankle inflammatory arthritis and bone involvement, of the calvarium and manubrium. Early and late syphilis in adults can manifest with articular and periarticular pathologies, including inflammatory arthritis, tenosynovitis, periostitis, and myositis. Higher clinical suspicion is needed for prompt diagnosis of syphilis in patients who are at risk and suspected of having an autoimmune disease. This report includes a review of the musculoskeletal manifestations of syphilis.