Curriculum reform is a significant approach to prepare schools to be effective in meeting contemporary societal needs and imperatives. Several countries around the world, therefore, engage in curriculum reform to enable schools to prepare children with the knowledge, skills, and competencies needed in the present and future society, but implementing change following a curriculum reform is often complex. In our study, we sought to understand how teachers respond to curriculum implementation following the introduction of the national pre-tertiary education curriculum framework (NPECF) in Ghana. We employed a concurrent, nested, mixed-design strategy (embedded design) using a sample of 352 randomly selected basic school teachers from six regions in Ghana. Data from surveys and interviews reveal that teachers consider the NPECF as relevant for Ghanaian educational fortunes; however, a myriad of classroom challenges come with the implementation process. We concluded that these challenges could affect the realization of the relevance of the NPECF if schools and teachers are not well resourced. We call the attention of duty bearers to the need to provide the necessary resources for the seamless implementation of the NPECF in Ghana. For policy adjustment, we recommended and proposed improvisation as an approach for teachers to utilize and exert autonomy and independence in the design and delivery of classroom instruction to sustain the NPECF in primary schools. Again, our study calls for coordination and collaboration among parents, civic society, and individuals across political divides to remain united to provide a solid foundation for education in Ghana.