Mechanical loading and hydrostatic pressure (HP) regulate chondrocytes' metabolism; however, how mechanical stimulation acts remain unclear. MicroRNAs (miRNAs) play an important role in cartilage homeostasis, mechanotransduction, and in the pathogenesis of osteoarthritis (OA). This study investigated the effects of a cyclic HP (1-5 MPa), in both normal and OA human chondrocytes, on the expression of , , , and , and of their target genes ( , , , and ). Furthermore, we assessed the possible involvement of Wnt/β-catenin pathway in response to HP. Chondrocytes were exposed to HP for 3h and the evaluations were performed immediately after pressurization, and following 12, 24, and 48 h. Total RNA was extracted and used for real-time PCR. β-catenin was detected by Western blotting analysis and immunofluorescence. In OA chondrocytes, HP induced a significant increase ( < 0.01) of the expression levels of , , and , and a significant reduction ( < 0.01) of at all analyzed time points. , , and were significantly downregulated following HP, while no significant modification was found for . β-catenin levels were significantly increased ( < 0.001) in OA chondrocytes at basal conditions and significantly reduced ( < 0.01) by HP. Pressurization did not cause any significant modification in normal cells. In conclusion, in OA chondrocytes, HP restores the expression levels of some miRNAs, downregulates MMP-13, ADAMTS-5, and HDAC-4, and modulates the Wnt/β-catenin pathway activation.