Colonization introduced devastating intergenerational effects on health that continue to impact “2-spirit” Indigenous people who experience poor health outcomes. Nurse practitioners (NPs) can improve health outcomes by addressing harmful implicit bias in health care settings, especially toward Indigenous gender-diverse individuals in Canada. Through cultural humility, NPs can implement meaningful clinical interventions that aim to promote positive health and wellness. For all NPs working with gender-diverse populations, important first steps include self-reflective practice and enhanced cultural knowledge. NPs can incorporate Indigenous healing strategies as clinical interventions and use strength-based approaches to provide safe, high-quality care for this vulnerable population.