Background: Parenteral penicillin is the first-line regimen for treating syphilis. However, allergic reactions and poor drug tolerance still present challenging problems with respect to use of this antibiotic.Methods: By searching PubMed and Embase databases, studies concerning ceftriaxone, erythromycin, minocycline, tetracycline, doxycycline, and penicillin for syphilis treatment were selected and included in eligible randomized controlled trials (RCT) and observational studies. A systematic review and network meta-analysis were performed. This study aimed to evaluate the efficacy and safety of ceftriaxone, erythromycin, minocycline, tetracycline, and doxycycline for syphilis treatment when compared with penicillin to determine which antibiotic could be a better substitute for penicillin. The Cochrane Handbook for Systematic Reviews of Interventions to assess the RCTs’ risk of bias and a modified Newcastle–Ottawa Scale (NOS) to assess the quality of each cohort study.Findings: This study included 17 articles, including three RCTs and 14 observational studies, involving 4485 syphilis patients. Estimated risk ratio (RRs) and 95% confidence interval (CIs) were used to compare their serological response rates. At the 6- and 12-month follow-ups, the serological response rate was compared by direct meta-analysis and network meta-analysis (NMA). Based on direct meta-analysis, the serological response rates at 3- and 24-month follow-ups were compared. Only three of the included studies reported drug safety. Due to the lack of reported data, this study only made a qualitative analysis of adverse drug reactions associated with syphilis treatment. The results of NMA indicated that the serological reaction rate of ceftriaxone was higher than that of penicillin (RR = 1·17; 95% CI 1·06–1·28) at the 6-month follow-up. Interpretation: In terms of serological response rate, ceftriaxone is as effective as penicillin for syphilis treatment. When compared with ceftriaxone, erythromycin, minocycline, tetracycline, and doxycycline, ceftriaxone appears to be a better alternative to penicillin.Funding Information: This study was supported by the National Natural Science Foundation of China ( No. 32060180, 82160304, 81560596, 81860644, and 31560051 ), Natural Foundation of Yunnan Province (2017FE467-001, 2019FE001-002).Declaration of Interests: We declare no competing interests.