Hemophilia is a rare congenital bleeding disorder caused by deficiency in coagulation factors VIII or IX, which is treated with prophylactic clotting factor concentrates. Nevertheless despite prophylaxis, spontaneous joint bleedings or hemarthroses still occur. The recurrent hemarthroses lead to progressive degradation of the joints and severe hemophilic arthropathy (HA) in patients with moderate and even mild forms of the disease. In absence of disease modifying treatment to stop or even delay HA progression, we aimed at evaluating the therapeutic potential of mesenchymal stromal cells (MSCs)-based therapy. We first developed a relevant and reproducible in vitro model of hemarthrosis relying on blood exposure of primary murine chondrocytes. We found that 30% whole blood for 4 days allowed to induce the characteristic features of hemarthrosis including low survival of chondrocytes, apoptosis induction, and dysregulation of chondrocyte markers in favor of a catabolic and inflammatory phenotype. We then evaluated the potential therapeutic effects of MSCs in this model using different conditions of coculture. Addition of MSCs improved the survival of chondrocytes when added either during the resolution or the acute phases of hemarthrosis and exerted a chondroprotective effect by enhancing the expression of anabolic markers, and reducing the expression of catabolic and inflammatory markers. We here provide the first proof-of-concept that MSCs may exert a therapeutic effect on chondrocytes under hemarthrosis conditions using a relevant in vitro model, thereby confirming a potential therapeutic interest for patients with recurrent joint bleedings.