OBJECTIVES To explore the experiences of Indigenous patient actors who co-created and enacted Indigenous patient scenarios in collaboration with medical school faculty. We critically examine the structures and systems in a medical school that mediate cultural safety for Indigenous patient actors. The Truth and Reconciliation Commission of Canada has called on medical schools and healthcare institutions to help address the intergenerational harms inflicted on Indigenous people by the Indian residential school (IRS) system. Institutions are striving to incorporate cultural competency, conflict resolution, human rights, and anti-racism education into their curricula. However, the structural inequities within undergraduate, postgraduate, and continuing medical education practices must be identified and challenged to ensure that medical education is authentic and culturally safe for those involved in the development and delivery of the Indigenous health curriculum. To explore potential structural inequities in the co-creation process of simulated cultural communication scenarios (SCCS), the Indigenous animators at Debajehmujig Storytellers and collaborating faculty and professional staff at the Northern Ontario School of Medicine University (NOSM U) examined cultural safety in their curriculum design and delivery process. METHODS We utilized the qualitative Indigenous research methodology of the Learning Circle to deconstruct the co-creation process and to explore the experience of cultural safety from the Indigenous animators’ perspective throughout the curriculum design and delivery process. RESULTS A framework for culturally safe co-creation practices with Indigenous people, rooted within Indigenous teachings of the Medicine Wheel, emerged from the qualitative data. CONCLUSIONS This framework has the potential to guide the practice of culturally safe co-creation of Indigenous patient simulations in medical education and healthcare workplace learning. While the Medicine Wheel teachings are held by specific Indigenous nations, we anticipate that the results and recommendations of this study will apply to Indigenous co-creators and academic medical educators internationally.