Background There are few data on the use of ceftriaxone in pregnant women diagnosed with syphilis. The aim of this study was to investigate the safety and efficacy of ceftriaxone as an alternative treatment option for syphilis during pregnancy. Methods A retrospective analysis of 79 pregnant women diagnosed with syphilis and treated with ceftriaxone was conducted. Results No cases of intolerance, Jarisch-Herxheimer reactions, or allergic reactions were recorded. The average time to seronegativation for secondary syphilis with symptoms was 6.14 months ± 2.76, and for latent forms, it was 7.52 months ± 1.84. Patients received no additional treatment. No serious adverse drug reactions were reported. Conclusions Data from our study support the use of ceftriaxone as an effective and safe alternative treatment for pregnant women diagnosed with syphilis when penicillin therapy is contraindicated or unavailable.