Myasthenia gravis (MG) is a serious inflammatory autoimmune disease with continuous production of autoantibodies against targets in the neuromuscular junctions, resulting in muscle weakness. Autoimmunity has long been presumed to be irreversible. The current therapeutic regimens do not always provide ideal treatment. Previously, we established that lignans could effectively inhibit inflammatory and malignant conditions including cancer. In this study, we used a mouse MG model with R97-116 peptide as the antigen to evaluate the effects of lignans on MG and investigate the molecular mechanisms of effects by multi-omics analyses. Lignans markedly alleviated muscle atrophy and elevated muscle strength. The gut microbiome composition was profoundly remodeled, the gut barrier was significantly ameliorated, and the levels of the anti-R97-116 IgG autoantibody were radically lowered, all signs suggesting reversed conditions of MG by lignans. Fecal microbiota transplantation experiments provided further evidence to validate roles of the gut microbiome in mediating the curative effects of lignans on MG. Mechanistically, the curative effects were associated with the inhibition of the Rap1gds1/Cdc42 signaling pathway.