Transforming growth factor beta (TGF-β) regulates a large number of biological processes, including proliferation, differentiation, immune response, and development. In addition, TGF-β plays important roles in some pathological processes, for instance, it is upregulated and activated in fibrosis and advanced cancer. Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that is activated when cells sense shortage of ATP and increase in AMP or AMP:ATP ratio. Activation of AMPK slows down anabolic processes and stimulates catabolic processes, leading to increased production of ATP. Furthermore, the functions of AMPK have been extended beyond energy homeostasis. In fact, AMPK has been shown to exert a tumor suppressive effect. Recent studies have demonstrated negative impacts of AMPK on TGF-β function. Therefore, in this review, we will discuss the differences in the biological functions of TGF-β and AMPK, and some pathological processes such as fibrosis, epithelial-mesenchymal transition (EMT) and cancer metastasis, as well as angiogenesis and heterotopic ossifications where TGF-β and AMPK exert opposite effects.