The primary aim of this study was to develop an American Indian and Alaska Native (AIAN) tailored research with human subjects curriculum that would increase the participation of AIAN members in research affecting their communities. We used a community-engaged research approach to co-design and evaluate a culturally tailored online human subjects curriculum among a national sample of AIAN community members (n = 244) with a standard nationally used online curriculum (n = 246). We evaluated pre- and post-test measures to assess group differences in ethics knowledge, perceived self-efficacy to apply such knowledge to protocol review, and trust in research. Analysis of regional tribal differences assessed curriculum generalizability. Using an 80% correct item cut-off at first attempt as passing criterion, the tailored curriculum achieved a 59.3% passing rate versus 28.1% in the standard curriculum (p < .001). For both arms, participants reported a significant increase in trust in research and in research review efficacy. Participants took less time to complete the training and reported significantly higher acceptability, satisfaction, and understandability of the curriculum for the tailored curriculum. This culturally tailored research ethics curriculum has the potential to increase participation in AIAN communities in research affecting tribal members. The AIAN curriculum achieved significantly higher levels of participants’ research ethics knowledge, self-efficacy in reviewing research protocols, trust in research, and completion of the training requirements. Culturally grounded training curricula may help remedy the impact of historical research ethics abuses involving AIAN communities that have contributed to mistrust of research and lack of community engagement in research.