Transforming growth factor-β (TGF-β) signaling plays a complex and dual role in regulating cellular senescence and tumor progression. In normal tissues, TGF-β acts as a tumor suppressor by regulating the cell cycle, inducing apoptosis, and maintaining the integrity of the extracellular matrix (ECM). These functions collectively restrict tumor initiation and support tissue homeostasis. However, in the tumor microenvironment, sustained TGF-β signaling frequently switches to a tumor-promoting role, driving tumor cell proliferation, metastatic dissemination, immune evasion, and therapy resistance. This review aims to clarify the dual role of TGF-β signaling in cellular senescence and tumor progression. It focuses on the molecular mechanisms that drive its transition between tumor suppression and tumor promotion in various biological contexts. We analyze the key determinants governing this functional switch, including tumor type, cellular environment, and signaling crosstalk. Furthermore, we critically evaluate the clinical challenges of therapeutic TGF-β targeting. We highlight emerging strategies to therapeutically modulate TGF-β signaling, focusing on precision medicine approaches that reconcile its tumor-suppressive and oncogenic functions. By providing a comprehensive understanding of TGF-β's dual role, this review offers new insights that may guide personalized cancer therapies and optimize treatment strategies for improved clinical outcomes.