Background. Podocyte injury plays a pathogenic role in the development of lupus nephritis (LN). Mesenchymal stem cells (MSCs) have shown promising therapeutic potential for LN. However, whether MSCs can prevent podocyte injury in LN remains unknown. Methods. Human umbilical cord-derived MSCs (UC-MSCs) were infused into lupus-prone B6.MRL-Faslpr (B6.lpr) mice to investigate the influences of UC-MSCs on podocyte injury in LN. Podocytes and macrophages were co-cultured with UCMSCs in vitro to study the mechanism by which UC-MSC protect podocytes. We further explored the effects of UC-MSCs on macrophage polarization. Results. We found that UC-MSCs promoted the expression of podocyte-specific markers, podocin and synaptopodin, in lupus-prone B6.lpr mice, along with the improvement of lupus renal pathology in terms of reduced IgG and C3 deposition in glomeruli and decreased anti-dsDNA antibody level. Besides, UC-MSC treatment decreased podocyte foot process effacement, as UC-MSCs-treated macrophages led to less podocyte injury in vitro. Interestingly, we further found that UC-MSCs-treated macrophages exhibited an antiinflammatory phenotype with higher expression of CD206, and lower expression of tumor necrosis factor-a and interleukin-1b. Additionally, UC-MSCs-treated lupus mice showed reduced renal macrophage infiltration and elevated CD206 expression in kidney. Conclusions. Our results demonstrated that UC-MSCs ameliorated LN by preventing podocyte injury possibly through reducing macrophage infiltration and polarizing macrophage into an anti-inflammatory phenotype.