The proliferation of information and divergent viewpoints in the 21st century requires an educated citizenry with the ability to critically evaluate information and make informed decisions. To meet this demand, adaptive epistemic understandings and beliefs about the nature of knowledge are needed, such as believing that scientific knowledge is evolving (development of knowledge) and needs to be justified through experimentation (justification of knowledge). Our study is the first to use nationally representative samples from 72 countries/regions (PISA 2015 database; N = 514,119 students) to examine how scientific epistemic beliefs about development and justification of knowledge in science are associated with students’ science motivation, achievement, and career aspirations in the STEM fields, as well as the cross-national generalizability of these relations. Results showed that (a) students who had more adaptive beliefs about knowledge being changeable and stemming from experimentation were likely to have high science self-efficacy, utility value, and particularly high intrinsic value; (b) epistemic beliefs were more strongly linked to science achievement than were motivational constructs; (c) the positive relation between epistemic beliefs and STEM-related career aspirations was largely explained by motivation and achievement; (d) the pattern of results generalized well across societies. Our findings suggest that epistemic beliefs are substantially positively associated with adolescents’ science learning, implying that developing effective interventions that focus on development and justification of knowledge would be fruitful for promoting science educational outcomes.