Osteoarthritis (OA) is a common disabling disease for which no effective pharmacological therapy exists. The progression of osteoarthritis is characterized by the loss of homeostasis in the cartilage. Since in the early stages of the disease, a phenotypic switch is seen in which articular chondrocytes become hypertrophic and promote degradation of the cartilage extracellular matrix, targeting this phenomenon might be the key to developing an effective therapy. To accelerate the identification of potential therapy, drug repurposing strategies are used. In this study we have used a novel approach by combining this with the signature reversing principle on single cell transcriptomics data aimed to reverse the hypertrophic phenotype of chondrocytes in osteoarthritic cartilage of patients. We identified 6 drugs predicted to reverse the hypertrophic phenotype of chondrocytes. Subsequent in vitro evaluation in human chondrocytes and cartilage explants demonstrated that Cobimetinib, a MEK1/2 inhibitor, indeed reduced chondrocyte hypertrophy-related and catabolic gene expression, such as SPP1 , COL10A1 , MMP13 and ADAMTS5 , while promoting collagen type 2 and aggrecan gene expression. Finally, single-cell RNA sequencing performed on osteoarthritic cartilage explants exposed to Cobimetinib ex vivo confirmed the anti-hypertrophic effect of the identified drug on hypertrophy-related gene expression and velocity analysis shows that cells are diverting toward a homeostatic cartilage cluster. This study is a proof of concept that open-access single cell omics data together with a drug repurposing strategy can identify drugs that target a specific cellular phenotype in diseases like osteoarthritis and could accelerate the drug discovery process.