The purpose of this study is to explore the relationship between life sciences teachers’ understanding of indigenous knowledge (IK) and their views of integrating Indigenous Knowledge in their teaching practice. A qualitative case study research approach was adopted, and purposive sampling strategy was used to select eight Grades 10–12 life sciences teachers in three peri-urban high schools. The Knowledge Synthesis model by Barnhardt and Kawagley is used as a framework for this study. Questionnaires and interviews were employed to collect qualitative data. Findings revealed that if teachers understand IK primarily as a body of inherited wisdom, they see the possibility of integration of IK as the use of local knowledge of the learners, as IK illustrations of life sciences curriculum constructs or as no integration in the science classroom at all. The latter group of teachers consider IK as an inherited body of knowledge in parallel with western science. If inclusion of IK is mandated, they suggest presenting IK separately, preferably by IK custodians. If teachers consider IK primarily as a holistic knowledge system including the physical and metaphysical world, they see integration opportunities at system level, for instance in teaching sustainability. Lastly, if IK is seen as a body of loosely connected science concepts, integration is possible where these concepts appear in the science curriculum documents. This study recommends that teachers should be involved in educational policy decision making since they have first-hand experience of learners in the classrooms and are involved with curricular and school matters. The implication of the findings from this study to science education is that the integration of both worldviews can be used as a tool to enhance science learning among high school learners taking life sciences by ensuring a culturally relevant science classroom.