Introduction: In March 2022, the Department of Obstetrics and Gynecology at the Centre hospitalier de l'Ouest guyanais (CHOG) reported to the French Guiana Regional Health Agency a sharp increase since 2021 in the number of pregnant women testing positive for syphilis, accompanied by an alarming rise in the number of cases of congenital syphilis. Hospital data confirmed that the increase was limited to western French Guiana and along the Maroni River. To better characterize the epidemiological situation of syphilis in western French Guiana since 2020 and the profile of women at risk, a supplementary investigation was launched by the French Guiana unit of Santé publique France. Method: A descriptive analysis of epidemiological trends in syphilis among the general population in western French Guiana from 2020 to 2022, as well as the characteristics of pregnant women followed at the CHOG in 2021 and 2022 who tested positive for syphilis, was conducted using biological data and medical records from the CHOG. Results: Between 2020 and 2022, an average of more than 9,000 people were screened annually at the CHOG, and the positivity rate increased 17-fold during this period. In 2021, 51 pregnant women who tested positive for syphilis during pregnancy were followed at CHOG, and among them, 22 gave birth to a child with confirmed or probable congenital syphilis. Over the 2021–2022 period, nearly 80% of pregnant women with syphilis were diagnosed in the second or third trimester of pregnancy, and 90% of them did not receive prenatal care in accordance with recommendations (number of visits and ultrasounds, trimester of first visit, and/or number of serology tests). Compared to women whose children were born free of the infection, those who gave birth to a newborn with congenital syphilis in 2021 were younger (21 years old versus 24 years old), the child was more often premature (38% of cases versus 11%), and treatment was administered later in the pregnancy. Nearly one in five women whose child was born with congenital syphilis became infected during pregnancy. Conclusion: The elimination of congenital syphilis is defined as a public health priority by the World Health Organization (WHO). The increase in hospitalizations for syphilis among pregnant women, accompanied by a decrease in hospitalizations for congenital syphilis among children in 2022 at the CHOG, appears to demonstrate the effectiveness of measures implemented as early as 2021 to improve screening and care for women with positive syphilis serology during pregnancy (3 screenings during pregnancy, protocol, and care pathway). Two major challenges in the fight against congenital syphilis in Western French Guiana have been identified: early screening for syphilis during pregnancy and the screening and treatment of sexual partners. Actions must be implemented to achieve the WHO target of fewer than 50 cases of congenital syphilis per 100,000 births by 2030.