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Simple Summary: In metastasis, cancer cells migrate away from the tissue where they first were generated and spread in other body compartments. During this process, stationary epithelial cells undergo multiple biochemical changes to become mesenchymal cells that present enhanced migratory abilities. Among numerous factors controlling the mesenchymal phenotype, TGFβ is one of the most important. Nevertheless, little is known about the mechanisms inhibiting the TGFβ biochemical pathways and metastasis remain the main reason of cancer mortality. We discovered that the protein called Kv11.1 potassium channel plays a major role in motility of colon cancer cells. We found that stimulating Kv11.1 activity with specific activator molecules produces a shutdown of the TGFβ pathway at its early stages. Consequently, cancer cell motility is suppressed by a reprogramming of the mesenchymal into epithelial phenotype. This research opens the possibility of using Kv11.1 activator molecules as a potential therapeutic strategy against metastatic colon cancer. Control of ionic gradients is critical to maintain cellular homeostasis in both physiological and pathological conditions, but the role of ion channels in cancer cells has not been studied thoroughly. In this work we demonstrated that activity of the Kv11.1 potassium channel plays a vital role in controlling the migration of colon cancer cells by reversing the epithelial-to-mesenchymal transition (EMT) into the mesenchymal-to-epithelial transition (MET). We discovered that pharmacological stimulation of the Kv11.1 channel with the activator molecule NS1643 produces a strong inhibition of colon cancer cell motility. In agreement with the reversal of EMT, NS1643 treatment leads to a depletion of mesenchymal markers such as SNAIL1, SLUG, TWIST, ZEB, N-cadherin, and c-Myc, while the epithelial marker E-cadherin was strongly upregulated. Investigating the mechanism linking Kv11.1 activity to reversal of EMT into MET revealed that stimulation of Kv11.1 produced a strong and fast inhibition of the TGFβ signaling. Application of NS1643 resulted in de-phosphorylation of the TGFβ downstream effectors R-SMADs by activation of the serine/threonine phosphatase PP2B (calcineurin). Consistent with the role of TGFβ in controlling cancer stemness, NS1643 also produced a strong inhibition of NANOG, SOX2, and OCT4 while arresting the cell cycle in G0/G1. Our data demonstrate that activation of the Kv11.1 channel reprograms EMT into MET by inhibiting TGFβ signaling, which results in inhibition of motility in colon cancer cells. [ABSTRACT FROM AUTHOR]