Background Methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacterales (CRE) impose the greatest burden among critical bacterial pathogens. Evidence for sex differences among antibiotic resistant bacterial infections is increasing but a focus on policy implications is needed. We assessed impact of CRE/MRSA on excess length of hospital stay, intensive care unit admission, and mortality by sex from a retrospective cohort study (n = 873) of patients in three Chilean hospitals, 2018-2021. Methods We used inverse-probability weighting combined with descriptive, logistic, and competing-risks analyses. We developed a sex-stratified deterministic compartmental model to analyse hospital transmission dynamics and the cost-effectiveness of nine interventions. We compared interventions based on the incremental costeffectiveness ratio (ICER) per quality-adjusted life year (QALY) gained and estimated net benefits. Findings The adjusted odds of women acquiring CRE and MRSA were 0.44 (0.28-0.70; p = 0.0013) and 0.73 (95% CI = 0.48-1.01; p = 0.050), respectively. Competing-risk models indicated higher mortality rates among women, compared to men. Mathematical model projections showed that pre-emptive isolation across all newly admitted high-risk men was the most cost-effective intervention (ICER = $1366/QALY and $1083/QALY for CRE and MRSA, respectively). Chromogenic agar coupled with MRSA decolonisation was the second most cost-effective intervention ($2099/QALY), followed by screening plus isolation or pre-emptive isolation strategies (ICER ranged between $2411/QALY and $4216/QALY across CRE and MRSA models). Probabilistic sensitivity analysis showed that strategies were ICER < willingness-to-pay in 80% of simulations, except for testing plus digestive decolonisation for CRE. At a 20% national hospital coverage at least $12.2 million could be saved. Interpretation Our model suggests that targeted infection control strategies would effectively address rising CRE and MRSA infections. Maximising health-economic gains may be achieved by focusing on control measures for men as primary drivers for transmission, thereby reducing the disproportionate disease burden borne by women. Copyright (c) 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).