Public Access Defibrillation (PAD) is the leading strategy in reducing time to first defibrillation in cases of Out-Of-Hospital Cardiac Arrest (OHCA), but PAD programs are underperforming considering their potentiality. Our aim was to develop an analysis and optimization framework, exploiting georeferenced information processed with Geographic Information Systems (GISs), specifically targeting residential OHCAs. The framework, based on an historical database of OHCAs, location of Automated External Defibrillators (AEDs), topographic and demographic information, proposes new strategies for AED deployment focusing on residential OHCAs, where performance assessment was evaluated using AEDs “catchment area” (area that can be reached within 6 min walk along streets). The proposed framework was applied to the city of Milan, Lombardy (Italy), considering the OHCA database of four years (2015–2018), including 8152 OHCA, of which 7179 (88.06%) occurred in residential locations. The proposed strategy for AEDs deployment resulted more effective compared to the existing distribution, with a significant improvement (from 41.77% to 73.33%) in OHCAs’ spatial coverage. Further improvements were simulated with different cost scenarios, resulting in more cost-efficient solutions. Results suggest that PAD programs, either in brand-new territories or in further improvements, could significantly benefit from a comprehensive planning, based on mathematical models for risk mapping and on geographical tools.