This study is a comparative analysis of 15-year-old students’ scientific literacy, and its association with the instructional strategies that students experience, across six OECD countries that participated in PISA 2015. Across the six countries, the study investigates the efficacy of inquiry-based instruction in science in contrast with two other instructional approaches to teaching secondary science: adaptive and teacher-directed teaching. The analysis shows that students who reported experiencing high frequencies of inquiry strategies in their classrooms consistently evidenced lower levels of scientific literacy across the six countries. Benchmark analysis also showed, common to all six countries, a strongly positive association between the frequency of teacher-directed and adaptive teaching strategies and students’ scientific literacy. Additionally, the study disaggregates PISA’s composite variable representing inquiry-based instruction and shows that different components of inquiry are differentially associated with students’ scientific literacy. We discuss the implications of these analyses for science teacher educators, science teachers, and educational policy makers. In doing so, we add nuance to our understanding of the efficacy of inquiry-based instruction in science, suggesting that some components, as conceptualised and assessed in PISA, seem to suggest greater attention and use, and others more moderated use.