Background: Cancer-related fatigue is one of the most common symptom experienced by cancer patients throughout their cancer trajectory. However, very little effort has been made within many oncology practices to assess this clinical problem and to provide timely nursing interventions to reduce its impact. While there have been tremendous advancements in the treatments of the disease aspects of cancer in term of medicine and advanced technology, basic assessment of related physiological concerns, such as fatigue, have not seen the same progress. Purpose: The purpose of this quality improvement project was to develop an evidence-based cancer-related fatigue assessment guideline and a screening protocol adopted from the National Comprehensive Cancer Network algorithm to assess cancer-related fatigue for oncology patients at their initial visit to the oncology unit toward timely intervention. Theoretical Framework: The ADAPTE collaboration model was used. This is an international framework that provides guidance on guidelines development and modification for healthcare providers. Method: This initiative began with a series of formal and informal conversations with major key stakeholders who were primarily the front-line oncology nurses at the practice unit. Based on the need of the unit, a consensus was reached to modify an existing clinical tool currently used to screen patients for emotional distress and to develop a clinical tool and guideline to screen cancer patient to reduce cancer-related fatigue as well. Outcome and Result: A clinical assessment tool was developed based on the patient population needs and the nursing staff concerns to yield an outcome that met the needs of this patient population. An evidence-based assessment guideline was introduced to key stakeholders and recommendations were made to integrate the new revised guideline into practice. The research department, professional practice, and the performance leadership continue to revise the current protocol to include continuous assessment of cancer-related fatigue into policy and procedure. Conclusion: This quality improvement project once implemented will benefit cancer patients as well as oncology practitioners by use of available resources and evidence-based guidelines to improve nursing practice and patient quality of life.