Abstract: The transforming growth factor-β (TGF-β) signaling pathway plays a bidirectional regulatory role in the development and progression of cancer. During cancer initiation, TGF-β can inhibit the growth and proliferation of epithelial cells and induce its apoptosis and thus play a critical role in inhibiting carcinogenesis. Therefore, the loss of response in epithelial cells to TGF-β inhibition is a landmark event during tumorigenesis. As the tumor progresses, TGF-β promotes cancer cell invasion, metastasis, drug resistance, and maintains cancer stem cell potential. Current research suggests that this functional transformation of TGF-β is associated with its interaction with multiple intracellular signaling pathways. On one hand, this crosstalk can reduce or eliminate the inhibitory and pro-apoptotic effects of TGF-β. On the other hand, it can also enhance the ability of TGF-β to promote tumor progression and aggravation. This review summarizes the molecular mechanism underlying the crosstalk between TGF-β and multiple intracellular signaling pathways during tumor progression and the effects of these interactions on tumor development.