This mixed‐methods research investigated teachers' perceptions of intrinsic factors (personal attributes of the teacher) and extrinsic factors (environmental) influencing the implementation of inquiry‐based science learning at township (underdeveloped urban area) high schools in South Africa. Quantitative data were collected by means of an adapted version of the Science Curriculum Implementation Questionnaire (SCIQ) (Lewthwaite, 2001). The adapted version was renamed the Scientific Inquiry Implementation Questionnaire (SIIQ) and was administered to 186 science teachers at township schools in South Africa. The teachers at a township school were then interviewed in order to solicit in‐depth information on the findings that emerged from the questionnaire analysis. The findings highlight a lack of professional science knowledge (content knowledge, pedagogical content knowledge, pedagogical knowledge, knowledge of students, educational contexts, curricular knowledge, and educational purposes) that contributes toward teachers' uncertainty in inquiry‐based teaching. Also, extrinsic factors such as school ethos, professional support, resource adequacy, and time serve as significant constraints in the implementation of inquiry‐based education at the school. The data collected from SIIQ provides a foundation for understanding at a high school level how factors influence the delivery of a curriculum underpinned by inquiry. © 2016 Wiley Periodicals, Inc. J Res Sci Teach 53: 598–619, 2016