Considerable research has demonstrated that teachers’ self-efficacy plays a major role in implementing instructional practices. Only few studies, however, have examined the interplay between how teachers’ self-efficacy and the challenges that lie outside their influence are related to their implementation of cognitive-activation strategies (CASs), especially in science classrooms. Using the Trends in Mathematics and Science Study 2015 data from science teachers in Grades 4, 5, 8, and 9, we explored the extent to which teachers’ self-efficacy in science teaching and the perceived time constraints explained variations in the enactment of general and inquiry-based CAS. Findings from the overall sample showed that highly self-efficacious teachers reported more frequent implementation of both general and inquiry-based CAS, whereas those who perceived strong time constraints reported a less frequent use of inquiry-based CAS. These relationships also existed across grade levels, except on the relations between perceived time constraint and inquiry-based CAS, which was only significant for the science teachers in Grade 9. We discuss these findings in light of variations in the core competencies of science curriculum, teachers’ competences, and the resources for science activities between primary and secondary education. We also point to the theoretical implications of this study for enhancing the conceptual understanding of generic and specific aspects of CAS and the practical implications for teacher education, professional development, and educational policy.