The mechanisms responsible for the inhibitory effects of mesenchymal stem cells (MSCs) on dendritic cells (DCs) are still poorly understood. Our investigation of the potential signaling pathways revealed for the first time that human umbilical-cord-derived MSCs (UC-MSCs) instruct DCs to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1. This subset of MSC-DCs exhibited a tolerogenic pattern, with a clear decrease in the expression of co-stimulatory molecules and the capacity to stimulate CD3(+) T cell proliferation and inflammatory factor secretion, and a significant increase in the production of inhibitory cytokine IL-10 and the ability to induce Treg cells and Th2 responses. Adoption of this tolerogenic pattern required the activation of SOCS1, which blocked DC maturation by impairing TLR4 signaling. The effects of UC-MSCs on SOCS1 activation were essentially mediated by the JAK-STAT pathway via IL-6 secretion. In summary, our data identify a new mechanism, involving the IL-6-mediated upregulation of SOCS1, by which UC-MSCs instruct DCs to acquire tolerogenic phenotypes.