Background: Congenital syphilis (CS) is an infectious disease caused by Treponema pallidum, which is transmitted through the placenta during pregnancy. Since 2001, a notable and consistent rise in the prevalence of CS cases has been observed, especially in low- and middle-income countries. Currently, information regarding the risk factors for this phenomenon has been scarcely addressed. Methods: A case-control study was conducted to analyze the risk factors for CS. Cases of CS were defined according to scenarios 1 and 2 from Centers for Disease Control criteria, while controls were considered those from scenarios 3 and 4. Data were collected from clinical records from 2016 to 2024 from a hospital in the metropolitan area of Monterrey, Mexico. Statistical analysis was conducted through SPSS V.22. Results: In total 297 syphilis-infected mothers were included in the analyses. Multivariable logistic regression analysis showed that CS was related to late maternal diagnosis, especially after birth [OR: 4.352 (1.313–14.423)]. Additionally, women with a high nontreponemal serum test titer (≥1:8) had an increased risk of delivering an infant with CS [OR: 4.380 (1.946-9.856)]. Infants born to mothers receiving adequate treatment [OR: 0.213 (0.101-0.450)] were a protective factor. Conclusion: CS is a major public health worldwide. Adequate treatment is critical for the prevention of CS. Strategies focusing on prenatal care, early diagnosis, and adequate treatment among those with high nontreponemal titer should be strengthened to prevent CS.