Methicillin‐resistant Staphylococcus aureus (MRSA) infections pose a significant challenge to U.S. healthcare facilities, but there has been limited study of initiatives to reduce infection and increase patient safety in community hospitals. To address this need, a multifaceted program for MRSA infection prevention was developed for implementation in 159 acute care facilities. This program featured five distinct tools—active MRSA surveillance of high‐risk patients, enhanced barrier precautions, compulsive hand hygiene, disinfection and cleaning, and executive champions and patient empowerment—and was implemented during 1Q–2Q 2007. Postintervention (3Q 2007–2Q 2008), 10.2% of patients with high‐risk for infection or complications due to MRSA had nasal colonization. Volume of disposable gown and alcohol‐based hand sanitizer use increased substantially following program implementation. Self‐reported rates, based on NHSN definitions, of healthcare‐associated central line‐associated bloodstream infections and ventilator‐associated pneumonia due to MRSA decreased 39% (p < .001) and 54% (p < .001), respectively. Infection rates continued to decrease during the follow‐up period (1Q–4Q 2009). This sustained improvement demonstrates that reducing healthcare‐associated MRSA infections in a large number of diverse facilities is possible and that a “bundled” approach that translates science into clinical and executive performance expectations may aid in overcoming traditional barriers to implementation.