Background: Esophageal cancer is the sixth most common cause of cancer-related mortality. There are two distinct histological types of esophageal cancer: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). In China, ESCC is the major subtype. Higher incidence of EAC is observed in western countries. Liquid biopsy detecting circulating tumor DNA is a non-invasive, real-time and highly sensitive approach that is able to identify and monitor the genetic mutations in tumor. Methods: In this study, we collected 490 Chinese esophageal cancer patients from 2018-2022 and characterized the mutational landscape of esophageal tumor tissue and circulating tumor DNA by whole exome sequencing or deep sequencing of targeted gene panel. The consistency of genetic alteration between tumor and ctDNA was also explored. Results: A total of 176 patients with plasma and 345 patients with cancer tissue were analyzed, among them, 31 patients had both ctDNA and tissue biopsy data. 277 genes with 1257 mutations were identified from plasma samples of 176 patients. The top frequently mutated genes were TP53 (89.1%), KMT2D (24.0%), SYNE1 (14.9%), NOTCH1 (14.3%), EP300 (13.7%), LRP1B (13.7%) and ZNF750 (10.3%). The mutation rates of these genes between ctDNA and tissue biopsy (N = 31 patients) were in concordance by Fisher's exact test (P > 0.05). Most frequent mutations were found in TP53 gene, which account for 89.1% of total plasma samples and 90.4% of tumor tissues. KMT2D gene mutations were detected in 24% of patients which encode histone methyltransferase that methylates the Lys-4 position of histone H3 and regulates transcriptional activation, indicating epigenetic regulation might be involved in the pathogenesis of esophageal cancer. Functional enrichment analysis was performed including Gene Ontology (GO) and KEGG analysis across all the three domains, Biological process, Molecular Function, and Cellular component. The KEGG terms with the highest enrichment score were PI3K−Akt signaling pathway, which is a key driver in carcinogenesis. In addition, we didn’t observe the mutually exclusive mutation or co-occurrence pattern of any gene pairs in our cohort. Conclusions: We demonstrated the utility of liquid biopsy to draw a ctDNA mutation profiling of esophageal cancer in Chinese patients. Genetic mutations identified from ctDNA showed consistency with mutations from tumor tissue.