The present study provides insights on the influence of family socioeconomic and school resources on principal leadership and, in turn, the influence of principal leadership on the science learning of students. The study uses data from the Programme for International Student Assessment (PISA) in 2015 (248,620 students and 9370 principals) from 35 developed countries. Three-level structural equation modeling indicates that family and school contexts influenced the enactment of principal leadership. Specifically, principals were able to exercise leadership (envisioning, conducting instructional management, promoting professional development, and advocating empowerment) in schools with more science resources. In contrast, principals seemingly addressed teacher capacity issues by envisioning and promoting the professional development and empowerment of teachers in schools with low socioeconomic status. The instructional management of principals was positively related to the enjoyment and interest of students in science, and those with high levels of such learning attitudes obtained high levels of science achievement. In contrast, the promotion of the professional development of teachers was negatively related to science enjoyment and interest of students.