OBJECTIVES: To identify and assess the effectiveness of national antibiotic optimization interventions in primary and secondary care in England (2013-2022). METHODS: A systematic scoping review was conducted. Literature databases (Embase and Medline) were used to identify interventions and evaluations. Reports included the UK AMR Strategy (2013-2018), National Action Plan (2019-2024) and English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) reports (2014-2022). The design, focus and quality of evaluations and the interventions' effectiveness were extracted. FINDINGS: Four hundred and seventy-seven peer-reviewed studies and 13 reports were screened. One hundred and three studies were included for review, identifying 109 interventions in eight categories: policy and commissioning (n = 9); classifications (n = 1); guidance and toolkits (n = 22); monitoring and feedback (n = 17); professional engagement and training (n = 19); prescriber tools (n = 12); public awareness (n = 17); workforce and governance (n = 12).Most interventions lack high-quality effectiveness evidence. Evaluations mainly focused on clinical, microbiological or antibiotic use outcomes, or intervention implementation, often assessing how interventions were perceived to affect behaviour. Only 16 interventions had studies that quantified effects on prescribing, of which six reported reductions. The largest reduction was reported with structural-level interventions and attributed to a policy and commissioning intervention (primary care financial incentives). Behavioural interventions (guidance and toolkits) reported the greatest impact in hospitals. CONCLUSIONS: Many interventions have targeted antibiotic use, each pulling different levers across the health system simultaneously. On the basis of these studies, structural-level interventions may have the greatest impact. Collectively, the combination of interventions may explain England's decline in prescribing but direct evidence of causality is unavailable.