This qualitative interpretive study explores issues and challenges influencing school improvement opportunities for Science and Mathematics in selected South African high schools through a systems leadership lens. Unstructured interviews were conducted with 13 participants comprising a principal, deputy principals, heads of department (HODs) for Science and Mathematics, and Mathematics and Physical Sciences teachers in four schools. The data from the interviews were analysed using the constant comparison techniques, allowing for inductive theme and concept building through abstraction. Findings show that participants, irrespective of school context, were generally eager to enhance the teaching and learning of Science and Mathematics. These challenges include the curriculum policy, the role of the district education office, professional development, learner-related challenges, and resources. It is recommended that the Department of Basic Education work closely with the relevant stakeholders, including teachers, to ensure context-friendly educational policies, thus ameliorating implementation challenges.