Abstract Temporomandibular joint osteoarthritis (TMJOA) is one of the most complex temporomandibular disorders. Cartilage matrix degradation results in the infiltration of nerves, blood vessels, and inflammatory cells, which disrupts chondrocyte function. Therapeutic strategies for TMJOA designed to maintain cartilage homeostasis remain largely unknown. Here, it is reported that orosomucoid 1 (ORM1) attenuated TMJOA progression by maintaining cartilage homeostasis. It is demonstrated that ORM1 is down‐regulated in the synovial fluid of patients with TMJOA and condylar cartilage of unilateral anterior crossbite (UAC) rats. Administration of ORM1 protein significantly inhibited cartilage matrix degradation and alleviated TMJOA progression in UAC rats. At the mechanistic level, ORM1 binds to vimentin (VIM), a type III intermediate filament cytoskeletal protein, and inhibits the mitogen‐activated protein kinase (MAPK) pathway, thereby significantly decreasing cartilage matrix degradation mediated through inhibiting the cartilage degradation markers matrix metalloproteinase 13 (MMP13) and MMP3, and maintaining cartilage homeostasis. Notably, inhibition of VIM in vivo also markedly improved TMJOA progression, including cartilage degradation and subchondral bone destruction. In conclusion, these findings demonstrate the important functions of ORM1 in maintaining cartilage homeostasis via suppressing VIM/MAPK/MMP signaling and suggest that ORM1 is a promising target for therapeutic intervention in TMJOA.