AbstractJoint repair remains a major challenge in orthopaedics. Recent progress in biomaterial design has led to the fabrication of a plethora of promising devices. Pre‐clinical testing of any joint repair strategy typically requires the use of large animal models (e.g., sheep, goat, pig or horse). Despite the key role of such models in clinical translation, there is still a lack of consensus regarding optimal experimental design, making it difficult to draw conclusions on their efficacy. In this context, the authors performed a systematic literature review and a risk of bias assessment on large animal models published between 2010 and 2020, to identify key experimental parameters that significantly affect the biomaterial therapeutic outcome and clinical translation potential (including defect localization, animal age/maturity, selection of controls, cell‐free versus cell‐laden). They determined that mechanically strong biomaterials perform better at the femoral condyles; while highlighted the importance of including native tissue controls to better evaluate the quality of the newly formed tissue. Finally, in cell‐laded biomaterials, the pre‐culture conditions played a more important role in defect repair than the cell type. In summary, here they present a systematic evaluation on how the experimental design of preclinical models influences biomaterial‐based therapeutic outcomes in joint repair.