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The chondrocyte mitochondrial dysfunction has been considered to be associated with the pathogenesis of joint diseases. Catalpol is an active traditional Chinese medicine ingredient named Di-Huang, which is used widely to treat different diseases. In this study, we found the addition of catalpol in chondrocytes induced the expression of crucial mitochondrial regulators, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor-1 (NRF1), and mitochondrial transcription factor A (TFAM). Catalpol promoted mitochondrial biogenesis, as revealed by the induction on the mitochondrial DNA/nuclear DNA (mtDNA/nDNA) and the expression of several mitochondrial genes including translocase of outer mitochondrial membrane 22 (Tomm22), translocase of outer mitochondrial membrane 70 (Tomm70), mitochondrial import inner membrane translocase subunit 50 (Timm50), NADH dehydrogenase [ubiquinone] iron-sulphur protein 3 (NDUFS3), adenosine triphosphate (ATP) synthase subunit D (ATP5d), and cytochrome B. Consequently, catalpol increased cytochrome c oxidase activity, the mitochondrial respiratory rate, and the extracellular ATP production, indicating that catalpol boosted mitochondrial function. Mechanistically, catalpol increased the activation of the cAMP-responsive element-binding protein (CREB), and the inhibition of CREB abolished catalpol-mediated promotion on mitochondrial biogenesis. In summary, this study demonstrated that catalpol has the potential to be used in the treatment of joint diseases.