There is an increasing drive in health care for creativity and innovation to tackle key health challenges, improve quality and access, and reduce harm and costs. Human-centered design (HCD) is a potential approach to achieving organizational innovation. However, research suggests the nursing workforce feels unsupported to take the risks needed for innovation, and leaders may not understand the conditions required to fully support them. The aim of this study was to identify enabling conditions that support frontline nurses in their attempts to behave as champions of innovation and change. An HCD workshop was undertaken with 125 nurses employed in clinical practice at Kaiser Permanente. The workshop included empathy mapping and semistructured questions that probed participant experiences with innovation and change. The data were collated and thematic analysis undertaken through a Grounded Theory approach. The data were analyzed to identify key enabling conditions. Seven enablers emerged: personal need for a solution; challenges that have meaningful purpose; clarity of goal and control of resources; active experimentation; experiences indicating progress; positive encouragement and confidence; and provision of psychological safety. These enablers were then translated into pragmatic guidelines for leaders on how the tools of HCD may be leveraged for innovation and change in health care.