This nationwide retrospective study in Japan aimed to identify risk factors and diagnostic indicators for congenital syphilis (CS) and improve diagnostic accuracy. Data were collected from 230 pregnant women diagnosed with syphilis and their infants between 2015 and 2024. Of these, 49 infants were diagnosed with definite or highly probable CS, while 73 infants with excluded CS served as the control group. Multivariable logistic regression analysis revealed two significant risk factors for CS: maternal treatment not completed more than 4 weeks before delivery (odds ratio [OR]: 7.20; 95% confidence interval [CI]: 1.38–37.56; p = 0.02) and elevated total IgM levels in the infant (>20 mg/dL) (OR: 65.31; 95% CI: 4.53–941.39; p = 0.002). When using infant rapid plasma reagin (RPR) ≥1 as a diagnostic indicator, sensitivity was 93.8% (n = 48). In contrast, the infant-to-mother RPR ratio ≥1 showed a lower sensitivity of 34.3%, with fewer cases available for analysis (n = 35) due to limited maternal data. These findings indicate that delayed maternal treatment and high total IgM levels in the infant are significant risk factors, while the infant’s RPR titre serves as a useful diagnostic indicator for CS.