Both aerobic exercise and glucosamine hydrochloride capsules (OTL) have a therapeutic effect on knee osteoarthritis, but their joint application has not been investigated. This study clarified the mechanism of the combined treatment in knee osteoarthritis. Aerobic exercise and OTL were used alone or in combination to treat papain-induced knee osteoarthritis model rabbits. Pathological changes of cartilage tissues, inflammatory cytokine content, glycosaminoglycan, and expressions of collagen II, cartilage differentiation-related genes and circUNK were analyzed by hematoxylin-eosin staining, Mankin score, Enzyme-linked immunosorbent assay, toluidine blue staining, Immunohistochemistry and qRT-PCR. The extracted chondrocytes were identified by Alcian Blue staining and immunohistochemistry and induced by iodoacetic acid (MIA) to establish osteoarthritis model. Effects of overexpressing or silencing circUNK on cell function and molecular changes in chondrocytes were analyzed by cell function experiments, qRT-PCR and Western blot. Rabbit modeling and intervention treatment were marked. Aerobic exercise or OTL treatment alone relieved the damage caused by knee osteoarthritis in terms of cartilage tissue lesions, Mankin score, inflammatory cytokine content, glycosaminoglycan, and expressions of collagen II, cartilage differentiation-related genes and circUNK. Combined application of aerobic exercise and OTL showed better synergistic treatment effects. Transfection of overexpressed circUNK could attenuate the MIA-induced effect on cell viability and apoptosis in chondrocytes by regulating genes related to differentiation and apoptosis. Aerobic exercise combined with glucosamine had a synergistic therapeutic effect on knee osteoarthritis. Overexpressing circUNK protected osteoarthritis model cells by regulating cartilage differentiation- and apoptosis-related genes. Copyright © 2021 Elsevier Inc. All rights reserved.