The purpose of this study was to investigate the factors contributing to senior secondary school learners’ poor performance in science subjects in the Mount Frere Education District of the Eastern Cape Province, South Africa. The literature analyses critically the existing knowledge based on factors contributing to poor performance of learners in science subjects and those factors that impact on learners’ positive attitudes towards science subjects. The study also identified literature on the following: motivational levels of science learners, teaching and learning strategies used in teaching science subjects, medium of instruction in the teaching and learning of science subjects, parental involvement in children’s learning, effects of lack of instructional materials on learner performance and learners’ attitudes towards science subjects. The study also examined the views of learners, teachers, Head of Department of sciences, parents and principals on factors contributing to poor performance of senior secondary school learners inscience subjects. The population for the study comprised of all principals, science teachers, science Head of Department, parents and science learners of the twenty six (26) senior secondary schools in the Mount Frere Education District. The principals, science teachers, science Head of Departments, parents of science learners and science learners in seven (7) senior secondary schools that offered science subjects were used as a sample in this study. The study employed the mixed method of quantitative and qualitative approaches. The research designs used were the survey and the case study. The instruments used were the questionnaires in which closed-ended questions were used to secure information and the interviews where open ended questions were used to collect data. The questionnaire as an instrument got tested in the pilot study to investigate the validity and reliability and also to identify possible deficiencies so as to rectify them. The responses were analyzed and presented in percentages using the Statistical Package for Social Science (SPSS) in the quantitative approach method of data analysis and in the qualitative data analysis process the researcher read through the data and became familiar with it and then identified the main themes and the next step was to examine the data in-depth and to provide detail descriptions of the participants’ words. The researcher also categorised and coded the data and then grouped them into themes and finally, interpreted the organised data into conclusion. The findings revealed that there was a lack of parental involvement, shortage of instructional materials, shortage of school laboratories, shortage of qualified science teachers and the learners’ negative attitudes towards science subjects. Recommendations were made concerning the above findings.