AbstractMechanical overload and chemical factors are both related to obesity‐induced progression of knee osteoarthritis. The circadian rhythm is related to the development of metabolic syndrome and the progression of osteoarthritis, and the core clock genes nuclear receptor subfamily 1 group D member 1 (NR1D1) and brain and muscle arnt‐like protein 1 (BMAL1) are dysregulated in cartilage from patients with osteoarthritis. Here, we focused on NR1D1 and investigated osteoarthritis‐related changes and gene expression in a mouse model of diet‐induced obesity. A high‐fat diet was provided to C57BL6/J mice, and changes in body weight, blood lipids, and gene expression were investigated. Destabilization of the medial meniscus or sham surgery was performed on mice fed a high‐fat diet or normal diet, and histological osteoarthritis‐related changes and NR1D1 expression were investigated. The effects of the NR1D1 agonist SR9009 were also assessed. Mice fed a high‐fat diet developed significant obesity and dyslipidemia. Nr1d1 and Bmal1 gene expression levels decreased in the liver and knee joints. Moreover, increased osteoarthritis progression and decreased NR1D1 protein expression were observed in high‐fat diet‐fed mice after surgical osteoarthritis induction. SR9009 decreased the progression of obesity, dyslipidemia, and osteoarthritis. Overall, obesity and dyslipidemia induced by the high‐fat diet led to osteoarthritis progression and decreased NR1D1 expression. Thus, NR1D1 may play an important role in obesity‐induced osteoarthritis.