Esophageal cancer is an aggressive malignancy with a poor prognosis. NUC7738, a cordycepin derivative, has shown promise in overcoming the limited in vivo efficacy of its parent compound. This study compares the anticancer effects of NUC7738 and cordycepin in esophageal cancer and explores the molecular mechanisms of NUC7738 action. In vitro, NUC7738 and cordycepin were tested on normal (Het1A) and esophageal cancer cell lines (ECA109, KYSE510) using Cell Counting Kit-8 (CCK-8) and colony formation assays. Apoptosis was confirmed by inhibitors and flow cytometry. Western blot was performed to detect apoptosis-related protein. KEGG analysis identified potential downstream signaling pathways, while qPCR, western blot, and immunofluorescence staining were applied to assess p53 expression and stability. In vivo, ECA109 cells were xenografted into nude mice, and tumor tissues were analyzed for p53 expression using Immunohistochemical staining. Finally, CCK-8, colony formation, and subcutaneous tumor xenograft assays in nude mice were employed to assess the synergistic effects of NUC7738 and cisplatin. The results revealed that NUC7738, although less effective than cordycepin in vitro, demonstrated superior anticancer activity in vivo. NUC7738 induced apoptosis by stabilizing p53 via ubiquitination, inhibiting tumor growth. Additionally, NUC7738 combined with cisplatin showed enhanced anticancer effects both in vitro and in vivo. These findings highlight greater potential of NUC7738 for clinical application, particularly in improving p53 stability and augmenting chemotherapeutic efficacy.