The inquiry-based strategy in science education is widely recommended and incorporated in practical work. However, contextual and intrinsic teaching challenges associated with practical investigations (inquiry-based practical work), occur in resource-constrained physical sciences classrooms in South Africa. The intrinsic challenges have previously been identified from the perspective of the pedagogical content knowledge framework and the concerns-based adoption model. In this article we present a novel approach, investigating the intrinsic challenges from a viewpoint of instructional design. The multi-method technique was used to collect data which was analysed by combining the deductive and the inductive approaches in thematic analysis. The findings consist of intrinsic teaching challenges in the initiation, planning, and implementation phases of practical investigations. Examples of the challenges include practical work being considered to have a confirmatory role, inadequacies linked to addressing learner safety, and unfamiliarity with well-known instructional models. While new challenges were identified, the findings add a new perspective to intrinsic challenges relating to practical investigations in the context of physical sciences education in South Africa. Also, the findings enhance global knowledge about the complexity of intrinsic teaching challenges linked to practical investigations. In addition, the findings inform teacher support while suggesting lines of future research linked to practical investigations in resource-constrained physical sciences classrooms in South Africa and beyond.