A recent trial showed that universal decolonization in adult intensive care units (ICUs) resulted in greater reductions in all bloodstream infections and clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) than either targeted decolonization or screening and isolation. Since regional health-care facilities are highly interconnected through patient-sharing, focusing on individual ICUs may miss the broader impact of decolonization. Using our Regional Healthcare Ecosystem Analyst simulation model of all health-care facilities in Orange County, California, we evaluated the impact of chlorhexidine baths and mupirocin on all ICU admissions when universal decolonization was implemented for 25%, 50%, 75%, and 100% of ICU beds countywide (compared with screening and contact precautions). Direct benefits were substantial in ICUs implementing decolonization (a median 60% relative reduction in MRSA prevalence). When 100% of countywide ICU beds were decolonized, there were spillover effects in general wards, long-term acute-care facilities, and nursing homes resulting in median 8.0%, 3.0%, and 1.9% relative MRSA reductions at 1 year, respectively. MRSA prevalence decreased by a relative 3.2% countywide, with similar effects for methicillin-susceptible S. aureus. We showed that a large proportion of decolonization's benefits are missed when accounting only for ICU impact. Approximately 70% of the countywide cases of MRSA carriage averted after 1 year of universal ICU decolonization were outside the ICU.