<p>Syphilis remains a major global public health challenge, particularly among men who have sex with men (MSM). Although penicillin is effective for treatment, primary prevention options are limited. Recent trials show that doxycycline post-exposure prophylaxis (doxy-PEP) can substantially reduce syphilis incidence, but its long-term population-level impact, effects on transmission dynamics and effective programme enrolment strategies remain unclear, especially when accounting real-world behavioural factors such as screening frequency, uptake, adherence and discontinuation. Here we develop a behavioural transmission-dynamic model calibrated using Bayesian methods with epidemiological and behavioural data from Singapore and England to characterize transmission dynamics in MSM, quantify the potential long-run public health impact, efficiency and robustness of alternative doxy-PEP programme enrolment strategies across different settings (for example, schools, sexual health clinics and risk groups) under varying behavioural patterns and epidemiological settings. Over 15 years, targeting MSM at high-risk (&gt;5 partners per year) at diagnosis is most efficient (averting 2.50 (95% credible interval 0.68–5.94) and 4.60 (2.12–7.79) cases per enrolment in Singapore and England, respectively). Broader strategies to enrol all MSM attending sexual health clinics into a doxy-PEP programme achieved larger total reductions but with much lower efficiency and can avert as few as 0.02 (0.00–0.23) and 0.04 (0.01–0.46) cases per enrolment, respectively. Findings were robust across different behavioural and future scenarios. In summary, doxy-PEP programmes should prioritize enrolling MSM at high-risk diagnosed with syphilis, while maintaining frequent STI screening every 3–4 months, and monitoring the emergence or amplification of tetracycline-resistant <i>Neisseria gonorrhoeae</i>.</p>