The NOD-like receptor family-pyrin domain containing 3 (NLRP3) inflammasome is an essential factor in enhancing inflammation and autoimmunity. Anesthetic isoflurane (ISO) exerts a novel pharmacological action in anti-inflammation. However, whether ISO hinders the pathogenesis of lupus nephritis (LN) by inhibiting NLRP3 inflammasome activation remains unclear. In this study, 12-week-old MRL/lpr and C57BL/6 mice were treated with and without 1.4% ISO for eight weeks. ISO administration significantly reduced mortality, serum anti-dsDNA level, renal immune complex deposition, and the ratio of Th17 to Treg cells in MRL/lpr mice. ISO treatment remarkably reduced the levels of blood urea nitrogen, proteinuria, interleukin (IL)-17, IL-1β, and tumor necrosis factor-α, as well as the infiltration of macrophages. ISO also abrogated renal NLRP3 inflammasome formation and activation. These results suggest that ISO may be a promising therapeutic agent for LN partly because it restricts NLRP3 inflammasome activation.