The objective of this work was to establish sustainable systems for quality improvement in an Academic Medical Center and Safety Net Hospital. High reliability principles of leadership engagement, a culture of safety, and sustainable performance improvement were used. Target areas for improvement were clinical outcomes for patients, public reputation scores, and lower cost of care. The system was based on annual focused goals with specific targets, improvement teams, transparent scorecards, and data driven work. Program visibility was championed by leaders. Consistent education on quality, safety, efficiency, and effectiveness for all employees created buy-in. Data review and accountability tracked progress, helped resource allocation, and defined next steps. In the first 5 years, all patient quality and safety metrics improved between 10% and 60%. This improvement resulted in higher CMS Star Ranking and Leapfrog patient safety grade. The next phase included maximizing value by expanding into hospital operations and finance with a focus on improved clinical documentation and reduced length of stay and cost of care. Clinical documentation improvement led to a 15% increase in comorbidity capture. This positively impacted reported outcomes and hospital payment by appropriate risk adjustment. Length of stay was addressed with a new care coordination program and physician-driven utilization review. High reliability principles are applicable in a resource limited healthcare system. Improved clinical and operational results were achieved through goal setting, improvement teams, and data driven projects leading to creation of an office of operational excellence.