Inquiry-based science education has been incorporated in science curricula internationally. In this regard, however, many teachers encounter challenges. The challenges have been characterised into those linked to the personal characteristics of these teachers (intrinsic challenges) and others associated with contextual factors (extrinsic challenges). However, this level of characterisation is inadequate in terms of appreciating the complexity of the challenges, tracking of their development, and discovering knowledge within specific categories. Against this background, the purpose of the research presented here was to characterise extrinsic challenges linked to the design and implementation of "inquiry-based practical work." In order to do so, we used a conceptual framework of teaching challenges based on Bronfenbrenner's ecological theory of human development. The data gathered using a multi-method case study of practical work in two South African high schools, was analysed by combining the data-driven inductive approach and the deductive "a priori" template of codes approach in thematic analysis. On this basis, the extrinsic challenges linked to the design and implementation of inquiry-based practical work that participants are confronted with, were found to consist of macrosystem challenges (such as a restrictive curriculum) and microsystem challenges. At the latter level, the challenges are material-related (e.g., lack of science education equipment and materials) or non-material-related (such as time constraints and the lack of access to interactive computer simulations). We have discussed the theory-, practice- and research-based implications of these results in relation to the design and implementation of inquiry-based practical work in South Africa and internationally.