Introduction: Disruptions of extracellular matrix (ECM) degradation homeostasis play a significant role in the pathogenesis of osteoarthritis (OA). Matrix metalloproteinase 13 (MMP13) and collagen II are impor-tant components of ECM. Earlier we found that quercitrin could significantly decrease MMP13 gene expression and increase collagen II gene expression in IL-1 beta-induced rat chondrocytes and human chon-drosarcoma (SW1353) cells. Objectives: The effects and mechanism of quercitrin on OA were explored. Methods: Molecular mechanisms of quercitrin on OA were studied in vitro in primary chondrocytes and SW1353 cells. An anterior cruciate ligament transection (ACLT) rat model of OA was used to investigate the effect of quercitrin in vivo. Micro-CT analysis and Safranin O-Fast Green Staining of knee joint & nbsp;samples were performed to observe the damage degree of tibial subchondral bone. Immunohistochemistry of knee joint samples were conducted to observe the protein level of MMP13, collagen II and p110a in articular cartilage. Results: In vitro, quercitrin promoted cell proliferation and delayed ECM degradation by regulating MMP13 and collagen II gene and protein expressions. Moreover, quercitrin activated the Phosphatidylinositol 3-kinase p110a (p110a)/AKT/mTOR signaling pathway by targeting p110a. We also firstly showed that the gene expression level of p110a was remarkably decreased in cartilage of OA patients. The results showed that intra-articular injection of quercitrin increased bone volume/tissue volume of tibial subchondral bone and cartilage thickness and reduced the Osteoarthritis Research Society International scores in OA rats. Meanwhile, immunohistochemical results showed that quercitrin exerted anti-OA effect by delaying ECM degradation. Conclusion: These findings suggested that quercitrin may be a prospective disease-modifying OA drug for prevention and treatment of early stage OA. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).