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Background Cancer is the world's second leading cause of death, but a significant advancement in cancer treatment has been achieved within the last few decades. However, major adverse effects and drug resistance associated with standard chemotherapy have led towards targeted treatment options. Objectives Transforming growth factor‐ß (TGF‐ß) signalling plays a key role in cell proliferation, differentiation, morphogenesis, regeneration, and tissue homeostasis. The prime objective of this review is to decipher the role of TGF‐ß in oncogenesis and to evaluate the potential of various natural and synthetic agents to target this dysregulated pathway to confer cancer preventive and anticancer therapeutic effects. Methods Various authentic and scholarly databases were explored to search and obtain primary literature for this study. The Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) criteria was followed for the review. Results Here we provide a comprehensive and critical review of recent advances on our understanding of the effect of various bioactive natural molecules on the TGF‐ß signalling pathway to evaluate their full potential for cancer prevention and therapy. Conclusion Based on emerging evidence as presented in this work, TGF‐ß‐targeting bioactive compounds from natural sources can serve as potential therapeutic agents for prevention and treatment of various human malignancies.