Esophageal adenocarcinoma (EAC) is the most prevalent type of esophageal malignancy in the United States (US) and the rate of occurrence continues to grow rapidly. As the prevalence of risk factors such as obesity and gastroesophageal reflux disease (GERD) rises, the rates of EAC are expected to continue rising as well. Unfortunately, the 5-year survival rate remains low and the lack of targetable, oncogenic drivers presents challenges in developing more effective and less toxic therapeutics. The current standard of care for EAC involves combinations of chemotherapeutics and radiation therapy that can cause severe side effects and often leads to refractory and relapsed disease. According to the cancer stem cell model, a small subset of the tumor cell population is responsible for cancer's ability to replicate, metastasize, and relapse. These cancer stem cells (CSCs) can self-renew and differentiate. Napabucasin, a "stemness" inhibitor, which works by inhibiting STAT3, has shown promising results in pre-clinical and clinical investigations across a variety of solid tumor types. Because a major barrier in treatment of EAC is the likelihood of relapse, targeting the CSC population that results in this phenotype is a therapeutic strategy of great interest. We hypothesize that employment of napabucasin to inhibit stemness through STAT3 represents a viable therapeutic strategy in the EAC setting. In this study, we investigated the efficacy of napabucasin on EAC cells. Napabucasin was shown to reduce phosphorylation of STAT3 as well as levels of MCL1, a cell survival protein downstream of STAT3, and levels of "stemness" markers Nanog, Sox2, and B-catenin via immunoblot analysis. Napabucasin monotherapy showed high efficacy in some EAC settings, with IC50 values in a clinically achievable range. The treatment in combination with cisplatin, a standard of care chemotherapeutic, resulted in reduced cell viability than either treatment alone indicating that a combination strategy could reduce the dosage of each drug needed. The data suggests that STAT3 inhibition in combination with current standard of care treatments could be a viable therapeutic strategy in EAC, and improve the dismal survival for these patients.