This study investigates the extent to which the implementation of the Skyline curriculum moderates the relationship between Exploring Computer Science (ECS) course-taking and high school students’ performance in biology, chemistry, and physics within Chicago Public Schools (CPS). Using a repeated cross-sectional design, data from two academic years (2021–2022 and 2022–2023) were analyzed with a three-level hierarchical linear model (HLM) to capture nested data structures—students within teachers within schools. The sample includes CPS high school students from grades 9 through 12, with student demographic and school-level variables as controls.  The findings reveal a consistent pattern across the three subjects. ECS course participation significantly improves science grades, highlighting the importance of computational thinking and problem-solving skills in supporting science learning. However, Skyline curriculum implementation does not significantly moderate the positive effects of ECS participation. To enhance Skyline’s effectiveness as a moderator, strategies such as targeted professional development for teachers, aligning computational activities with the cognitive demands of each science subject, and fostering collaboration between curriculum developers and educators are critical. These measures could optimize the integration of computational thinking into science instruction, benefiting both teachers and students.  This study underscores the need to refine science curricula to better integrate computational concepts in ways that align with the unique requirements of each discipline. It also highlights the importance of providing targeted professional development to support effective implementation. The findings offer valuable insights for improving integrated STEM education and advancing related policy and practice.