Background: Noncommunicable chronic diseases account for the highest number of mortalities across the globe and are responsible as the greatest contributor to medical healthcare expenses. To create new medicines to fight these diseases, we need to fully understand the pathological mechanisms behind them in addition to the usual therapeutic targets. TGF-β has become a promising target for therapy to help a number of fatal diseases, and it may be possible to challenge it therapeutically by either increasing its activity or decreasing it. Objective: The present review aims to highlight the therapeutic importance of TGF-β as a potent target to cure multiple chronic diseases, such as cardiovascular disorders and malignant tumors. It also mentions pharmacologically approved drugs as well as drugs that are currently under investigation. Methods: Our approach entailed a comprehensive literature review employing keywords such as “TGF-β signaling pathway,” “myocardial fibrosis,” and “neurological disorders.” We sourced pertinent information from reputable databases, including PubMed, Scopus, and Elsevier. The TGF-β signaling pathway is what makes cancer grow and spread, as well as fibrotic proliferation in many organs, including the lungs, heart, kidneys, and liver. In such diseases, enhanced signaling is implicated in the progression. However, in the case of nervous disorders such as Parkinson’s disease and Alzheimer’s disease, TGF-β signaling is found to be hampered. Both augmentation and inhibition of TGF-β are proven to be useful as therapeutic targets to counter these diseases. Conclusion: This review aims to provide an in-depth analysis of the historical development of research on TGF-β and the molecular mechanisms that underlie its biosynthesis, activation, and signaling transmission. Our objective is to offer a comprehensive and systematic understanding of TGF-β signaling, building on previous knowledge and recent updates, and to encourage further research in this area. DOI:10.2174/0115743624339476250212114656