Human placenta-derived mesenchymal stem cells (pMSCs) are considered a good source for cell therapy. The purpose of this study was to observe whether the transplantation of human pMSCs would affect the treatment of lupus nephritis (LN)-prone MRL/lpr mice. Multiple injections (at the 16th, 18th, and 20th week of age) of 1 × 106 pMSCs were administered. Urine was collected to evaluate proteinuria and urine creatinine levels. Blood was collected for the measurement of serum antinuclear antibody (ANA) and anti-double-stranded DNA (dsDNA) antibody levels. Renal tissues were collected for histological staining and examination by light and electron microscopy quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western Blot. The results confirmed that pMSC treatment reduced the severity of 24-h proteinuria, decreased the production of anti-dsDNA antibodies, and ameliorated renal pathological changes in MRL/lpr mice. Furthermore, pMSCs reduced renal inflammation by inhibiting the expression of nuclear factor kappa B (NF-κB) and then downregulating the expression of tumor necrosis factor-α (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1). Therefore, our present study demonstrated a protective effect of pMSCs against renal injury and inflammation in MRL/lpr mice.