ABSTRACT Nursing physical fatigue is a critical issue that may lead to degradation of care delivery and ultimately result in medical errors. This issue is equally relevant due to the looming shortage of nurses, which has been linked to the physical demands and potential occupational hazards intrinsic to the profession; as well as to the graying of the nursing workforce who experiences gradual loss of strength and agility that accompanies aging as time in the career advances. In a hospital Emergency Department, the level of nursing physical fatigue can potentially reach its threshold in light of challenging workloads, scope of job assignments and demanding schedules. While in other safety-sensitive industries such as aviation and nuclear plants, similar concerns have been the object of systematic research and addressed with consequent regulations, just recently, the healthcare sector has been engaged in further investigations. This study proposed to explore the linkage between Emergency Department design-layout and nursing physical fatigue. It was expected that further understanding on this relationship would support evidence-based design propositions linking nursing wellness, job satisfaction, and performance to a higher quality of care and improved patient safety levels. To this end, data collection was performed during four weeks in a community-based hospital. A convenience sample of twenty-four eligible nurses was invited to participate in this two-part study. The first section consisted of the completion of a self-administered questionnaire, which assessed nurses' perception of the impact of working conditions on nursing physical fatigue. The second section included the monitoring, through the use of accelerometers, of nurses' actual activity intensity levels during three consecutive shifts. Among other findings, data demonstrated that nurses perceive several attributes or components of the built environment as potential contributors to physical fatigue. In addition, various operational practices and organizational protocols were linked to physical fatigue. Contrary to nurses' perception of physical fatigue, their actual physical activity levels fell mostly between sedentary or light intensity ranges. This paradox offers the opportunity for design interventions that, in alignment with operational practices and organizational protocols will enhance nurses' performance and improve nurses' retention.