Esophageal cancer (EC) is a common malignancy with a poor prognosis worldwide.There are two core pathways that repair double-strand breaks, homologous recombination (HR) and non-homologous end joining (NHEJ) and numerous proteins are recognized that affect the occurrence of HR and NHEJ. Altered DNA damage response (DDR) pathways are associated with cancer susceptibility and affect therapeutic response and resistance in cancers. DDR pathway alterations in EC are still poorly understood. Therefore, the identification of alterations in specific genes in DDR pathways may potentially result in novel treatments for resistant cancers, especially EC. In this review, we aimed to focus on different aspects of DNA damage and repair processes in EC. Also, we reviewed new therapeutic strategies via targeting DNA repair machinery components.