Chondrocyte loss is a prominent feature of osteoarthritis (OA). Autophagy is indispensable in maintaining the metabolic activities of cells exposed to deleterious stress. The contribution of microRNA signaling to chondrocyte autophagy in OA development remains elusive. We uncovered an association between poor autophagy and increased miR-128a expressions in articular chondrocytes of patients with end-stage knee OA and in a rat anterior cruciate ligament transection (ACLT) model for OA development. Cartilage matrix degradation and severe OA histopathology was evident upon forced miR-128a expression within the articular compartment. Intra-articular injections with miR-128a antisense oligonucleotide stabilized chondrocyte autophagy and slowed ACLT-mediated articular tissue destruction, including cartilage erosion, synovitis, osteophyte formation, and subchondral plate damage. In vitro, miR-128 signaling hindered Atg12 expression, LC3-II conversion, and autophagic puncta formation through targeting the 3′-untranslated region of Atg12. It increased apoptotic programs, diminishing cartilage formation capacity of articular chondrocytes. Inactivating histone methyltransferase EZH2 reduced methyl histone H3K27 enrichment in the miR-128a promoter and upregulated miR-128a transcription in inflamed chondrocytes. Taken together, miR-128a-induced Atg12 loss repressed chondrocyte autophagy to aggravate OA progression. EZH2 inactivation caused H3K27 hypomethylation to accelerate miR-128a actions. Interruption of miR-128a signaling attenuated chondrocyte dysfunction and delayed OA development. Our data provide new insights into how miR-128a signaling affects chondrocyte survival and articular cartilage anabolism and highlight the potential of miR-128a targeting therapy to alleviate knee OA.