Quercetin has been preliminarily proven to serve as a potential agent for the treatment of osteoarthritis (OA). However, its effects and potential mechanisms on the pathological process of OA are not very clear. This study aimed to study the protective effect of quercetin on OA. Lipopolysaccharide (LPS)-treated chondrocytes (C28/I2 cell) and anterior cruciate ligament transection with partial medial meniscectomy-treated Wistar rats were used as models of OA in vitro and in vivo. Cell counting kit-8 (CCK-8 kit), flow cytometry, enzyme-linked immunosorbent assay (ELISA) kit, western blot, dichlorodihydrofluorescein diacetate (DCFH-DA) kit, thiobarbituric acid (TBA) test, toluidine blue staining, Hematoxylin eosin (HE) staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining were used to evaluate cell viability, cell apoptosis, inflammatory cytokines level, protein expression, reactive oxygen species (ROS) level, malondialdehyde (MDA) content, morphological changes, and chondrocyte apoptosis of cartilage, respectively. Results showed that quercetin could reduce LPS-induced C28/I2 cell apoptosis, extracellular matrix (ECM) degradation, and cell pyroptosis, and overexpression of nucleotide-binding domain and leucine-rich-repeat-containing (NLR) family, pyrin domain-containing 3 (NLRP3) revealed that quercetin reduced chondrocyte apoptosis and ECM degradation by inhibiting NLRP3-mediated pyroptosis. Furthermore, quercetin could reduce chondrocyte apoptosis and ECM degradation, and inhibit NLRP3-mediated pyroptosis through blocking oxidative stress. It was further confirmed in the rat OA model that quercetin alleviated OA by blocking oxidative stress, reduces chondrocyte pyroptosis, apoptosis, and ECM degradation. In conclusion, quercetin inhibited OA via blocking oxidative stress-induced chondrocyte pyroptosis in models of OA in vitro and in vivo.