Osteoarthritis (OA) is a progressive degenerative joint disease, and to date, no disease-modifying OA drug exists. Amniotic membrane and umbilical cord products have been used clinically in several diseases due to their anti-inflammatory and antiscarring properties. In the present study, we sought to evaluate whether a particulate amniotic membrane and umbilical cord (AM/UC) matrix could aid in attenuating disease progression. Lewis rats underwent medial meniscus transection (MMT) to induce OA. Two weeks after surgery, animals received intra-articular injections (50 μL) of either 50 or 100 μg/μL particulate AM/UC or saline control and were subsequently euthanized 1 or 4 weeks later. Cartilage degeneration was assessed using both histological scoring methods and equilibrium partitioning of an ionic contrast agent-microcomputed tomography (EPIC-μCT). EPIC-μCT analysis demonstrated that overall cartilage destruction was attenuated, with a significant increase in both cartilage thickness and volume as well as a significant decrease in total lesion area in animals injected with either dose of particulate AM/UC at 1 week, but only a high dose at 4 weeks postinjection. Osteoarthritis Research Society International (OARSI) histology scores of tibial sections corroborated EPIC-μCT results. Overall joint destruction was attenuated in animals injected with either dose of AM/UC tissue compared with saline-injected control animals at 1 week postinjection. Only high-dose AM/UC-injected animals continued to show less overall joint destruction by 4 weeks postinjection. Intra-articular injection of particulate AM/UC tissue attenuates cartilage degradation in a rat MMT model of OA, suggesting that it may be able to slow joint destruction in patients with OA.