Systemic lupus erythematosus (SLE) is a chronic inflammatory systemic autoimmune disease. Recurrent relapses of disease and development of long-term organ damage are two key unsolved clinical problems. The pathogenesis of SLE is complex, and it is increasingly recognized that the overactive immune system driving the disease presents metabolic abnormalities, offering novel therapeutic opportunities. Although both the short- and long-term survival rates of SLE patients have increased tremendously over the past 50 years, the mortality rate of SLE patients remains 2–4 times higher than that of healthy individuals. Recently, a number of mechanistic studies have identified potential benefits of metformin in the treatment of SLE. Metformin has been repurposed for multiple autoimmune conditions because it reverses aberrant metabolism in an array of immune cell lineages, such as T-helper 1 cells, T follicular helper cells, T-helper 17 regulatory cells, plasmablasts, neutrophils, and plasmacytoid dendritic cells. The mode of action of metformin is multifaceted. It can exert a regulatory effect through the suppression of oxidative phosphorylation by inhibiting mitochondrial electron transport chain complex 1, and through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, or via AMPK-independent pathways.