Congenital syphilis (CS) remains a major public health problem, and its incidence is increasing worldwide. Retrospective, observational, and descriptive study of cases with CS and their mothers at a tertiary-level hospital in Mexico from 2017 to 2022. Medical records of patients with CS and a structured collection of epidemiological, clinical, and laboratory data were analyzed and classified in the Centers for Disease Control scenarios as confirmed, probable, less probable, or unlikely. One hundred eighty cases were diagnosed with a compatible definition of congenital syphilis, and we identified 43 (21.21%) confirmed proven. Among those proven cases, 15.6% had hematological, 13.3% skin, 12.2% liver, 6.7% pulmonary, 6.6% neurological, 5.8% eye, 5.6% bone, and 0.6% hearing involvements. According to the clinical stages of maternal syphilis, 119 (66.1%) were in the late latent phase, 49 (27.2%) in the early latent phase, 7 (3.9%) in the secondary stage, and 5 (2.8%) in the primary stage. Mothers with tertiary syphilis were not detected. Regardless of negative antenatal screening, health care workers should consider the diagnosis of congenital syphilis. Infants are still undiagnosed at birth, and only a tiny percentage exhibits symptoms. The wide range of clinical manifestations of this preventable infection can be misdiagnosed for various other diseases, causing diagnostic delays that can have serious consequences.