BACKGROUND: Defibrillation in the critical first minutes of out-of-hospital cardiac arrest (OHCA) can significantly improve survival. However, timely access to automated external defibrillators (AEDs) remains a barrier. OBJECTIVES: The authors estimated the impact of a statewide program for drone-delivered AEDs in North Carolina integrated into emergency medical service and first responder (FR) response for OHCA. METHODS: Using Cardiac Arrest Registry to Enhance Survival registry data, we included 28,292 OHCA patients ≥18 years of age between 1 January 2013 and 31 December 2019 in 48 North Carolina counties. We estimated the improvement in response times (time from 9-1-1 call to AED arrival) achieved by 2 sequential interventions: 1) AEDs for all FRs; and 2) optimized placement of drones to maximize 5-minute AED arrival within each county. Interventions were evaluated with logistic regression models to estimate changes in initial shockable rhythm and survival. RESULTS: Historical county-level median response times were 8.0 minutes (IQR: 7.0-9.0 minutes) with 16.5% of OHCAs having AED arrival times of <5 minutes (IQR: 11.2%-24.3%). Providing all FRs with AEDs improved median response to 7.0 minutes (IQR: 6.2-7.8 minutes) and increased OHCAs with <5-minute AED arrival to 22.3% (IQR: 16.4%-30.9%). Further incorporating optimized drone networks (326 drones across all 48 counties) improved median response to 4.8 minutes (IQR: 4.3-5.2 minutes) and OHCAs with <5-minute AED arrival to 56.3% (IQR: 46.9%-64.2%). Survival rates were estimated to increase by 34% for witnessed OHCAs with estimated drone arrival <5 minutes and ahead of FR and emergency medical service. CONCLUSIONS: Deployment of AEDs by FRs and optimized drone delivery can improve AED arrival times which may lead to improved clinical outcomes. Implementation studies are needed.