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This doctoral project is an evaluation of a quality improvement initiative that applied a mixed method approach to evaluate the impact of the Comprehensive Unit-based Safety Program (CUSP) on hand hygiene (HH) compliance and healthcare-associated infection rates. The project was conducted in the United States of America (USA), Florida in an acute care hospital. The practice problem addressed was the persistent low adherence to HH protocols among healthcare staff, a critical issue in nursing practice due to its direct link to preventable patient harm. Quantitative data demonstrated a substantial reduction in infection rates following the implementation of the CUSP program. Specifically, from fiscal year (FY) 2022 to FY 2024, central line-associated bloodstream infections declined from 5 to 1, MRSA cases from 3 to 0, CAUTI cases from 1 to 0, and C-DIFF cases from 9 to 0. HH compliance concurrently improved from an estimated 58% in FY 2022 to 80% in FY 2024. Qualitative data reflected improved teamwork, clearer communication, and strengthened accountability. The outcomes portray the value of CUSP in advancing nursing practice, fostering equitable patient care, and contributing to positive social change.