Abstract Background Global recognition of antimicrobial resistance (AMR) as an urgent public health problem has galvanized national and international efforts. Chief among these are interventions to curb the overuse and misuse of antibiotics. However, the impact of these initiatives is not fully understood, making it difficult to assess the expected effectiveness and sustainability of further policy interventions. We conducted a systematic review to summarize existing evidence for the impact of nationally enforced interventions to reduce inappropriate antibiotic use in humans. Methods We searched seven databases and examined reference lists of retrieved articles. To be included, articles had to evaluate the impact of national responsible use initiatives. We excluded studies that only described policy implementations. Results We identified 34 articles detailing interventions in 21 high- and upper-middle-income countries. Interventions addressing inappropriate antibiotic access included antibiotic committees, clinical guidelines and prescribing restrictions. There was consistent evidence that these were effective at reducing antibiotic consumption and prescription. Interventions targeting inappropriate antibiotic demand consisted of education campaigns for healthcare professionals and the general public. Evidence for this was mixed, with several studies showing no impact on overall antibiotic consumption. Conclusions National-level interventions to reduce inappropriate access to antibiotics can be effective. However, evidence is limited to high- and upper-middle-income countries, and more evidence is needed on the long-term sustained impact of interventions. There should also be a simultaneous push towards standardized outcome measures to enable comparisons of interventions in different settings.