Fibrosis refers to the excessive deposition of extracellular matrix components in the processes of wound repair or tissue regeneration after tissue damage. Fibrosis occurs in various organs such as lung, heart, liver, and kidney tissues, resulting in the failure of organ structural integrity and its functional impairment. It has long been thought to be relentlessly progressive and irreversible process, but both preclinical models and clinical trials in multiorgans have shown that fibrosis is a highly dynamic process. Transforming growth factor-beta (TGF-β) is a superfamily of related growth factors. Many studies have described that activation of profibrotic TGF-β signaling promotes infiltration and/or proliferation of preexisting fibroblasts, generation of myofibroblasts, extracellular matrix deposition, and inhibition of collagenolysis, which leads to fibrosis in the pathological milieu. This review describes the effect of TGF-β signaling in fibrotic-associate lung, heart, liver, and kidney tissues, followed by a detailed discussion of canonical and non-canonical TGF-β signaling pathway. In addition, this review also discusses therapeutic options by using natural products and chemical agents, for targeting tissue fibrosis via modulating TGF-β signaling to provide a more specific concept-driven therapy strategy for multiorgan fibrosis.Copyright © 2022 Elsevier B.V. All rights reserved.