Antibiotic stewardship programs (ASP) are used in hospitals, long-term care, and ambulatory settings to reduce healthcare-associated infections and antibiotic-associated adverse events. This article focuses on the implementation of AHRQ’s Safety Program for Improving Antibiotic Use in acute care hospitals across the US in 2018. Participating hospitals reported the evidence-based content was helpful in raising awareness of the importance of antibiotic stewardship and creating local guidelines. Hospitals also reported challenges such engaging frontline staff and limited resources in smaller hospitals. Strategies to address challenges are discussed.