Hit, Lead & Candidate Discovery This study investigated the effects of a natural phenolic compound quercetin on surgical-induced osteoarthritis (OA) in rabbits. Forty-eight New Zealand White rabbits were used to establish OA model by Hulth modified method, and subsequently randomized into untreated OA group (treatment was drinking water), celecoxib treated group (celecoxib 100 mg kg by gavage), and quercetin treated group (25 mg kg by gavage). Sixteen nonoperated rabbits served as the normal controls (drinking water was given). The treatment (length: 4 weeks) started on the 5th week postoperation when the OA pathological changes were manifested. Expressions of superoxide dismutase (SOD), matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in serum, synovial fluid, and synovial tissue were measured at 8 and 12 weeks postoperation. Pathological analysis was performed with synovial tissue section and Osteoarthritis Research Society International histopathology grading and staging scores were determined. The quercetin treated group showed higher SOD and TIMP-1 expressions but lower MMP-13 expression than untreated OA group in the serum, synovial fluid and synovial tissues (p < .05). There was no significant difference in the SOD, MMP-13 and TIMP-1 expressions between the quercetin-treated and celecoxib-treated groups. The MMP-13/TIMP-1 ratio of the quercetin treated group was significantly lower than that of the untreated OA group (p < .05). Quercetin can up-regulate SOD and TIMP-1, down-regulate MMP-13, and improve the degeneration of OA through weakening the oxidative stress responses and inhibiting the degradation of cartilage extracellular matrix.