Thyroid hormone (TH) is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSCs). TH concentrations in the blood are stable, but the action of the deiodinases (D2-D3) provides cell-specific regulation of TH activity. Deregulation of deiodinase function and TH status has been implicated in tumorigenesis. Therefore, we investigated the role of TH metabolism and signaling in colorectal CSCs (CR-CSCs), where deiodinases control cell division and chemosensitivity . We found that increased intracellular TH concentration through D3-depletion induced cell differentiation and sharply mitigated tumor formation. Upregulated BMP4 expression and concomitantly attenuated Wnt signaling accompanied these effects. Furthermore, we demonstrate that BMP4 is a direct TH target, and is involved in a positive autoregulatory feedback loop that modulates TH signaling. Collectively, our findings highlight a cell autonomous metabolic mechanism by which CR-CSCs exploit TH signaling to facilitate their self-renewal potential, and suggest that drug-induced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression.