BACKGROUND: Emerging research has provided evidence suggesting the potential influence of governance on the development and spread of antimicrobial resistance (AMR), accounting for significant disparities observed both between and within countries. In our study, we conducted an ecological analysis to investigate the relationship between governance quality, antibiotic consumption, and AMR across Italian regions. METHODS: By leveraging data from three distinct sources at the regional level, we compiled a comprehensive dataset comprising: AMR proportions for three specific pathogen-antibiotic combinations in the year 2021, antibiotic consumption data for systemic use in the year 2020, and the 2021 European Quality of Government Index (EQI) and its corresponding pillars. Employing mediation analysis, we investigated the potential mediating role of antibiotic consumption in the association between the EQI and an average measure of AMR. RESULTS: Our analysis revealed substantial variation in the percentages of AMR across different regions in Italy, demonstrating a discernible North-to-South gradient concerning both antibiotic usage and governance quality. The EQI exhibited a statistically significant negative correlation with both antibiotic consumption and AMR percentages, encompassing both specific combinations and their average value. Regions characterized by higher levels of governance quality consistently displayed lower values of antibiotic consumption and AMR, while regions with lower governance quality tended to exhibit higher levels of antibiotic use and AMR. Furthermore, we observed a significant total effect of the EQI on average AMR (ß = - 0.97; CI - 1.51; - 0.43). Notably, this effect was found to be mediated by antibiotic consumption, as evidenced by a significant indirect effect (ß = - 0.89; CI - 1.45; - 0.32). CONCLUSIONS: These findings draw attention to the regional disparities observed in AMR levels, antibiotic consumption patterns, and governance quality in Italy. Our study also highlights the mediating role of antibiotic consumption in the relationship between governance quality and AMR. This underscores the significance of implementing focused interventions and policies aimed at improving governance quality and promoting responsible antibiotic use.