INTRODUCTION: Limited information on costs and the cost-effectiveness of hospital interventions to reduce antibiotic resistance (ABR) hinder efficient resource allocation. METHODS: We conducted a systematic literature review for studies evaluating the costs and cost-effectiveness of pharmaceutical and non-pharmaceutical interventions aimed at reducing, monitoring and controlling ABR in patients. Articles published until 12 December 2023 were explored using EconLit, EMBASE and PubMed. We focused on critical or high-priority bacteria, as defined by the WHO, and intervention costs and incremental cost-effectiveness ratio (ICER). Following Preferred Reporting Items for Systematic review and Meta-Analysis guidelines, we extracted unit costs, ICERs and essential study information including country, intervention, bacteria-drug combination, discount rates, type of model and outcomes. Costs were reported in 2022 US dollars ($), adopting the healthcare system perspective. Country willingness-to-pay (WTP) thresholds from Woods et al 2016 guided cost-effectiveness assessments. We assessed the studies reporting checklist using Drummond's method. RESULTS: Among 20 958 articles, 59 (32 pharmaceutical and 27 non-pharmaceutical interventions) met the inclusion criteria. Non-pharmaceutical interventions, such as hygiene measures, had unit costs as low as $1 per patient, contrasting with generally higher pharmaceutical intervention costs. Several studies found that linezolid-based treatments for methicillin-resistant Staphylococcus aureus were cost-effective compared with vancomycin (ICER up to $21 488 per treatment success, all 16 studies' ICERs<WTP). Infection control measures such as hand hygiene and gown usage (ICER=$1160/QALY or $4949 per ABR case averted, all ICERs<WTP) and PCR or chromogenic agar screening for ABR detection were highly cost-effective (eg, ICER=$1206 and $1115 per life-year saved in Europe and the USA). Comparisons were hindered by within-study differences. CONCLUSION: Robust information on ABR interventions is critical for efficient resource allocation. We highlight cost-effective strategies for mitigating ABR in hospitals, emphasising substantial knowledge gaps, especially in low-income and middle-income countries. Our study serves as a resource for guiding future cost-effectiveness study design and analyses.PROSPERO registration number CRD42020341827 and CRD42022340064.