Objective To analyze the clinicopathological characteristics of differentiated early cardia cancer and to evaluate the short‑term and long‑term efficacy of endoscopic submucosal dissection (ESD). Methods A total of 329 patients (331 lesions) who underwent ESD at Nanjing Drum Tower Hospital from October 2014 to December 2019 and were pathologically confirmed as differentiated early cardia cancer were included in the study and followed up. The endoscopic and pathological data of patients were reviewed to analyze the clinicopathological characteristics of differentiated early cardia cancer. The short‑term (including en bloc resection rate, curative resection rate and incidence of short‑term complications) and long‑term efficacy (including incidence of metachronous cancer, recurrence and distant metastasis, and overall survival rate) of ESD was evaluated. Results The ratio of male to female in 329 patients with differentiated early cardia cancer was 4∶1, and their age was 65.69±8.02 years. Tumor diameter of ≤2.0 cm accounted for 65.9% (218/331). Most lesions were located on the posterior wall (50.5%, 167/331), followed by the minor curve (36.3%, 120/331). The endoscopic morphology of 0-Ⅱc type accounted for 49.5% (164/331). There were 69.8% (231/331) lesions confined to the mucosal layer. The en bloc resection rate was 100.0% (329/329), and the curative resection rate was 83.3% (274/329). Short‑term complications occurred in 28 patients (8.5%). With a median follow‑up time of 39 months, 11 patients (3.3%) developed metachronous cancer, 2 (0.6%) developed distant metastasis, and no recurrence occurred. Seven patients died, and the overall survival rate during the follow‑up period was 97.9% (322/329). The survival rate of patients with curative resection and additional surgery was 100.0% (3/3), while that without additional surgery was 99.3% (269/271). The survival rate of patients with non‑curative resection and additional surgery was 96.0% (24/25), and that without additional surgery was 86.7% (26/30). Conclusion Most differentiated early cardia cancers are well‑differentiated adenocarcinomas, with less than 2 cm in diameter at the time of diagnosis with a low rate of ulcer and vascular invasion. ESD is safe and effective for the treatment of differentiated early cardia cancer with a high rate of curative resection, fewer intraoperative and postoperative complications, low incidences of metachronous cancer, distant metastasis and recurrence, and a high overall survival rate. However, additional surgical treatment is recommended for patients with non‑curative resection.