The generation of reactive oxygen species has a pivotal role in both acute and chronic glomerular injuries in patients with lupus nephritis. As the transcription factor Nrf2 is a major regulator of the antioxidant response and is a primary cellular defense mechanism, we sought to determine a role of Nrf2 in the progression of lupus nephritis. Pathological analyses of renal biopsies from patients with different types of lupus nephritis showed oxidative damage in the glomeruli, accompanied by an active Nrf2 antioxidant response. A murine lupus nephritis model using Nrf2(+/+) and Nrf2(-/-) mice was established using pristine injection. In this model, Nrf2(-/-) mice suffered from greater renal damage and had more severe pathological alterations in the kidney. In addition, Nrf2(+/+) mice showed ameliorative renal function when treated with sulforaphane, an Nrf2 inducer. Nrf2(-/-) mice had higher expression of transforming growth factor β1 (TGFβ1), fibronectin, and iNOS. In primary mouse mesangial cells, the nephritogenic monoclonal antibody R4A activated the nuclear factor-kappa B (NF-κB) pathway and increased the level of reactive oxygen species, iNOS, TGFβ1, and fibronectin. Knockdown of Nrf2 expression aggravated all aforementioned responses induced by R4A. Thus, these results suggest that Nrf2 improves lupus nephritis by neutralizing reactive oxygen species and by negatively regulating the NF-κB and TGFβ1 signaling pathways.