Diabetes and other metabolic and inflammatory comorbidities are highly associated with osteoarthritis. However, whether early-life hyperglycemia exposure affects susceptibility to long-term osteoarthritis is still unknown. The purpose of this study was to explore the fetal origins of osteoarthritis and provide insights into early-life safeguarding for individual health. This study utilized STZ to induce intrauterine hyperglycemia and performed DMM surgery on the knee joints of the offspring mice to induce accelerated osteoarthritis. Cartilage degeneration-related markers, as well as the expression levels of mitochondrial respiratory chain complexes and mitophagy genes in the adult offspring mice, were investigated. In vitro, mitochondrial function and mitophagy of chondrocyte C28/I2 cells stimulated under high glucose conditions were also evaluated. The methylation levels of the sirt3 gene promoter region in the articular cartilage of intrauterine hyperglycemia-exposed offspring mice were further analyzed. In this study, we found that the intrauterine hyperglycemic environment could lead to an increase in individual susceptibility to osteoarthritis in late adulthood, mainly due to persistently low levels of Sirt3 expression. Downregulation of Sirt3 causes impaired mitophagy in chondrocytes and abnormal mitochondrial respiratory function due to a failure to clear aged and damaged mitochondria in a timely manner. Overexpressing Sirt3 at the cellular level or using Sirt3 agonists like Honokiol in mouse models can partially rescue mitophagy disorders caused by the hyperglycemic environment and thus alleviate the progression of osteoarthritis. Our study revealed a significantly increased susceptibility to OA in the GDM offspring, which is partly attributed to exposure to adverse factors in utero and ultimately to the onset of disease via epigenetic modulation. All data are available from the corresponding authors upon reasonable request.