Depression is a common and serious illness that impairs the health of individuals and societies globally. It is associated with a significant economic burden, with productivity losses exceeding $40 billion dollars annually in the United States (U.S.) alone. This project focused on the use of a systematic, data-driven approach to improve the screening rate for depression in an academic, metropolitan cancer center located in North Texas. A multidisciplinary team collaboratively applied Lean Six Sigma education, methods, and tools within oncology and psychiatry clinics to address the increased risk of depression among oncology patients. Improving the standardization of screening and follow-up processes, resulted in a 44% sustained increase in the depression screening and follow-up performance rate. This improvement was verified to be statistically significant through the use of control charts toward the end of the project.