Esophageal squamous cell carcinoma (ESCC) cells migrate from their initial site of origin, ultimately forming metastasis and causing death. The selective inhibition of ESCC cell movement has not been possible to date. Here we demonstrate that the small molecule therapeutic agent KBU2046 inhibits the characteristic migration and invasion of ESCC cells induced by chemokine gradients, having no effect on cell proliferation. After demonstrating that KBU2046 inhibits human ESCC metastasis in a murine model, we showed that it doesn't inhibit the in vitro efficacy of chemotherapeutic agents used clinically, going on to demonstrate maintenance of cisplatin efficacy when combined with KBU2046 in a murine model. Mechanistic studies demonstrated that KBU2046 inhibited epidermal growth factor (EGF)-mediated phosphorylation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) on its Ser166 activation motif. RIPK1 was shown to be necessary for KBU2046 efficacy. However, this was shown to be dependent upon cell context, and was also shown to be dependent upon level of RIPK1 expression, both supporting the presence of additional therapeutically sensitive regulatory pathways. Mass spectrometry analysis of ESCC cells demonstrated that KBU2046 selectively altered the expression of proteins involved in cell motility. Integrin αV (ITGAV) is overexpressed in ESCC, was decreased by KBU2046, and its knockdown inhibited ESCC cell migration and invasion, which was necessary for KBU2046 efficacy. We demonstrate that ESCC's motility can be inhibited, and KBU2046 inhibits motility in an Integrin αV-dependent manner, and that combining anti-motility and cytotoxic agents is a high valuable therapeutic strategy for ESCC that should be further developed.Copyright © 2025. Published by Elsevier B.V.