α-mangostin, a polyphenolic xanthone derivative of mangosteen, has been reported to possess multiple therapeutic properties, such as anti-cancer, anti-allergy and anti-inflammatory activity. However, its anti-inflammatory effects in autoimmune diseases such as lupus nephritis (LN) remain unclear. In this study, we want to investigate the therapeutic effect of α-mangostin in LN. First, we elucidated the retinoic acid receptor related orphan receptor gamma t (RORγt) inhibitory activity of α-mangostin in cell-based assay and T helper 17 (Th17) differentiation in vitro assay. Then, we established a pristane-induced LN mouse model and randomly divided these into a normal control group, model control group, α-mangostin group and prednisone acetate group. Finally, anti-double-stranded DNA (anti-dsDNA) level in serum was detected by enzyme-linked immunosorbent assay, interleukin (IL)-17A and interferon (IFN)-γ expression in spleen cells by flow cytometry; histomorphology examination of kidneys was performed by periodic acid-Schiff staining and immunofluorescence analysis with an anti-immunoglobulin G (anti-IgG) and anti-IgM antibodies. We found that α-mangostin inhibited RORγt transcription activity in a cell-based assay and also polarized Th17 cells in an in vitro induction experiment. Our results also showed that α-mangostin could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in the α-mangostin-treated group mice than in the model group mice. Thus, α-mangostin demonstrated its potential as a candidate therapeutic drug for LN and other Th17-mediated autoimmune diseases by inhibiting the function of Th17. © 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.