Fibrosis is a pathological feature of most chronic diseases and leads to the dysfunction of various organs. However, there is currently no effective method for treating fibrosis. In recent years, a small gas, sulfur dioxide (SO2), which can be generated endogenously in mammals, as been found to have vasorelaxation activity, improve cardiac function and decrease myocardial injury. Endogenous SO2 also mediates the process of fibrosis. Inhibition of endogenous SO2 can aggravate small pulmonary artery remodeling and abnormal collagen accumulation. SO2 treatment significantly improves pulmonary fibrosis and pulmonary arterial remodeling. Overexpression of the key enzymes associated with endogenous SO2 generation, aspartate aminotransferase (AAT) 1 and AAT2, mimics the effect of SO2 on the down-regulation of collagen synthesis, while AAT1 or AAT2 knockdown aggravates abnormal collagen accumulation in vascular smooth muscle cells (VSMC5). SO2 also improves myocardial fibrosis induced by myocardial infarction or diabetes in rats, and inhibits myocardial fibroblast proliferation and migration by the extracellular signal-regulated protein kinase pathway. The mechanisms underlying the inhibition of fibrosis by SO2 are related to its antioxidant effect, anti-inflammation effect, improvement in cardiac function, and cell proliferation inhibition. Therefore, SO2 has a potential therapeutic effect on fibrosis.