Since scientific literacy has become a key goal in science education, many people have argued in favor of the incorporation of inquiry in science education. However, scattered in the literature are extrinsic and intrinsic teaching challenges linked to the design and implementation of inquiry‐based practical work (IBPW) in secondary school science classrooms. The purpose of this systematic literature review was to characterize and clarify the intrinsic challenges. From an instructional design perspective, the characterization of the challenges yielded four primary categories. The categories consist of initiation‐phase challenges (such as unfavorable views regarding science and practical work), planning‐phase challenges (including difficulties involved in designing IBPW), implementation‐phase challenges (e.g., persuading learners to reflect on their experiences and findings), and summative evaluation‐phase challenges which include concerns linked to the grading of practical inquiry. In the different categories, the challenges are linked to gaps in various aspects of teacher competencies especially in the context of the TPACK framework. The aspects include content knowledge (CK) (such as science content and scientific inquiry); in addition to technological knowledge (TK) linked to standard technologies. Also included is pedagogic CK (including orientation toward science teaching). Moreover, some of the intrinsic challenges are linked to gaps in skills (including pervasive classroom management and practical skills); in addition to values (such as commitment). These results have theory‐, practice‐, and research‐based implications.