The concept of hybridisation is one of the most difficult concepts for chemistry students to grasp at all levels of learning. Research showed the students conceptual difficulty ranged from their lack of the prerequisite knowledge for grasping the topic hybridisation to chemical bond formation and orientations of atomic orbitals. This study investigated the difficulties Senior High School Students face in learning hybridisation. The study adopted a mixed-method approach using the sequential exploratory design. Purposive sampling was used to select six schools that offer elective chemistry subject. Simple random sampling was then used to select 120 Senior High School form 1 students to take part in the study. Convenient sampling was used to interview 24 students from the sample. Hybridisation Achievement Test (HAT) and Semi-structured interviews were self-constructed and used to collect data. Descriptive statistics and Content analysis were used to analyse the data. Results showed that, majority of students had difficulties in explaining the concept of hybrid orbitals, writing the electron configuration of [subscript 6]C, explaining the effect of hybridisation on formation of chemical bonds in [subscript 6]C, and type of hybridisation and shapes of compounds such as NH[subscript 3], OF[subscript 2], BCl[subscript 3], CO[subscript 2], SiO[subscript 2], C[subscript 2]H[subscript 2], BeF[subscript 2] and C[subscript 2]H[subscript 4]. The study also showed that students had difficulties in explaining and demonstrating the formation of C = C double bond in ethene and other compounds. Equally students were challenged in demonstrating the differences between the formation of sigma and pi bonds in compounds. Students had difficulties in using electron orbital diagrams to explain the shape of CO[subscript 2] as linear. The study concluded that Senior High School form 1 chemistry students in the Upper West Region of Ghana lacked the most basic and fundamental concept of hybridisation. Teachers need to use conceptual change instructional approaches to teach hybridisation in order to foster students' understanding and reduce misconceptions.