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, has 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 (VSMCs). 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.