Abstract Background Ganoderma lucidum ( Lingzhi ; LZ) and San - Miao - San (SMS) are Chinese medicines (CMs) used to treat inflammatory ailments and numbing syndrome/arthralgia syndrome ( Bi Zheng ), respectively. Given that the main symptoms of systemic lupus erythematosus (SLE) include inflammation of the joints, joint pain, edema and palpitations of the heart because of problems associated with Bi Zheng , it was envisaged that LZ and SMS could be used as potential treatments for this autoimmune disease. This study aims to investigate the anti-inflammatory activity of a combination formulation containing LZ and SMS (LZ–SMS) in SLE mice. Methods Female adult Balb/c mice of 20–24 weeks of age were used as normal mice (n = 10), whereas female MRL/lpr mice of 12–24 weeks of age were divided into three groups (n = 10 in each group), including mild, moderate and severe SLE mice groups. The clinical characteristics of the SLE and Babl/c mice (i.e., body weight, joint thickness, lupus flare, proteinuria, leukocyturia and lymphadenopathy) were assessed. The plasma concentrations of anti-nuclear antibody (ANA) and anti-double stranded DNA antibody (anti-ds-DNA) were analyzed by an enzyme-linked immunosorbent assay, whereas the concentration of several key cytokines (IFN-γ, TNF-α, IL-6, IL-10, IL-2, IL-27, IL-12P70, IL-17A and IL-21) were analyzed by a Luminex multiplex assay. The gene expression profiles for differentiation of the T helper (Th) lymphocytes in splenic CD4 + Th cells were assessed by RT-qPCR. Flow cytometry was used to measure the percentages of CD4 + CD25 + Foxp3 + Treg cells and CD19 + CD5 + CD1d + IL-10 + regulatory B (Breg) cells (IL-10 + Bregs). Results Concentrations of anti-ds-DNA in the plasma samples collected from the LZ–SMS-treated (500 mg/kg/day oral administration for 7 days followed with 50 mg/kg/day intraperitoneal administration for 7 days), moderate and severe SLE mice decreased significantly compared with the PBS treated mice ( P