We propose a process of contextualization based on seven empirically derived contextualization principles, aiming to provide opportunities for Indigenous Mexican adolescents to learn science in a way that supports them in fulfilling their right to an education aligned with their own culture and values. The contextualization principles we empirically derived account for Nahua students’ cultural cognition, socialization, and cultural narratives, thus supporting Indigenous students in navigating the differences between their culture and the culture and language of school while learning complex science concepts such as natural selection. The process of curricular contextualization we propose is empirically driven, taking culture, and socialization into account by using multiples sources (cognitive tasks to explore teleology, ethnographic observation of students’ community and classroom, and interviews with students and community members) and builds on the scholarship in Culturally Relevant Pedagogy and Indigenous Education. We used these principles to redesign a middle school biology unit on natural selection to make it more culturally relevant for Nahua students. The enactment of this unit resulted in students being engaged in science learning and achieving significant learning gains. The significance of this study lies in presenting evidence that learning science in culturally relevant ways supports the learning of challenging biology concepts. We provide evidence that Western science can be learned in ways that are more aligned with Indigenous students’ Traditional Indigenous Knowledge, thus informing the implementation of educational policies aiming to improve the quality of secondary education for Indigenous adolescents. Our proposed contextualization principles can benefit students of all cultural identities who feel that their religion, language, or traditional knowledge are not aligned with school science, facilitating their access to culturally relevant science education. © 2017 Wiley Periodicals, Inc. J Res Sci Teach 9999:XX–XX, 2017.