Purpose <p>Osteoarthritis (OA) remains a significant challenge in the United States, with nearly 20% of adults experiencing some degree of the disease. Current treatment methods aim to mitigate pain and delay disease progression; however, they lack regenerative potential. A deeper understanding of the driving factors that cascade the initiation of OA is still missing, and there is an even greater lack of regenerative approaches to reverse OA damage. There is a critical need to develop biomaterial models of OA that can mimic the local tissue microenvironment in 3D to elucidate the role of extracellular matrix (ECM) signals on OA progression and identify therapeutic approaches. Decellularized ECM (dECM) has surfaced as an exciting platform to design and develop biomaterials that can model the local healthy or diseased joint microenvironment in vitro and have the potential to serve as implantable treatments for clinical applications. This review focuses on the various approaches for processing ECM into dECM, and fabricating dECM biomaterials for the study and treatment of OA. We emphasize novel uses of dECM as in vitro models and in vivo therapeutics and the opportunities that exist in the use of dECM to further understand OA progression and treatment.</p> Lay Summary <p>Osteoarthritis (OA) is a degenerative joint disease affecting millions worldwide, with current treatments aimed at managing symptoms without the ability to reverse the disease. There is a need to better understand the factors influencing disease progression that will allow the development of novel therapeutics. Decellularized extracellular matrix (dECM), a natural tissue-derived material that supports healing and reduces inflammation, poses a promising material platform to study OA in vitro and in vivo while also serving as an implantable therapeutic. This review highlights how dECM can be used to model OA and develop treatments that restore damaged cartilage.</p> Graphical Abstract <p></p>