Background Esophageal cancer patients can experience co-occurring, related symptoms labeled symptom clusters. This study aimed to identify symptom clusters and explore which SCs independently affect the quality of life (QoL) among esophageal cancer patients. Methods This cross-sectional study was performed in Shenyang, China, from February 2021 to February 2022. Finally, 118 esophageal cancer patients effectively completed the survey. Questionnaires’ information included the Functional Assessment of Cancer Therapy-General (FACT-G), the MD Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI), the Multidimensions Scale of Perceived Social Support, and demographic and clinical characteristics. Exploratory factor analysis with principal axis factoring was used to identify symptom clusters, and multiple regression analysis was employed to analyze the influencing factors of QoL. Results The mean score of FACT-G was 69.88 (SD = 17.85) among 118 esophageal cancer patients. Four symptom clusters were identified: psychological-somatic, dysphagia, fatigue-pain, and gastrointestinal symptom clusters. Results of regression analysis indicated a significant impact on QoL for chemotherapy (β = 0.140, P < 0.045), psychological-somatic symptom cluster (β = − 0.329, P = 0.013), and social support (β = 0.409, P < 0.001) after adjusting demographic and clinical characteristics. The linear combination explained 47.8% of the variance in QoL. Conclusions There is a critical need to emphasize the importance of psychological-somatic symptoms clusters management programs and increasing social support to improve QoL in esophageal cancer patients.