The Notch signaling pathway plays a critical role in embryonic development, self-renewal of stem cells, and carcinogenesis. Aberrant Notch signaling has been linked to a wide variety of cancers, and can either suppress or promote tumors depending on the cell type and the context. Increasingly it is being realized that Notch signaling not only involves in the pathogenesis and development of esophageal adenocarcinoma (EAC), it also promotes the growth of EAC cells and also involved in the maintenance of EAC cancer stem cells. The efficacy of gamma-secretase inhibitor (GSI) in EAC treatment could have a major impact on easing the burden of this devastating disease. Therefore, it appears that inhibition of Notch sensitizes EAC cells to chemotherapeutic agents, which should lead to a better and more durable response to neoadjuvant chemotherapy (NAC). In this review, we bring to highlight how Notch plays a role in the development, tumorigenicity, and stemness of EAC cells, and how Notch signaling pathway could be a promising therapeutic target for the treatment of human EAC.