Background Esophageal cancer (EC) is one of the leading contributors to the global burden of cancer, and the underlying mechanism is still unknown. Recently, there has been a growing interest in understanding modifiable psychosocial risk factors, particularly depression, to prevent EC and reduce morbidity and mortality. However, related research is sparse and has been ignored. The study was designed to assess the association between depression and EC in China. Methods From 2017 to 2019, a population-based multicenter study was conducted in high-risk regions of EC. Participants underwent a free endoscopy screening. If the endoscopic results were suspicious, a pathological biopsy was applied to confirm. Depression was measured with Patient Health Questionnaire-9 (PHQ-9). In addition, information on demographic characteristics and risk factors was collected from participants by trained interviewers using uniform questionnaires. Results After Endoscopy and pathologic diagnosis, 15,936 participants in high-risk regions of EC (ECHRRs) were enrolled, 10,907 (68.44%) of which were diagnosed health, 4048 (25.40%) with esophagitis, 769 (4.83%) with low-grade intraepithelial neoplasia (LGIN), 157 (0.99%) with high-grade intraepithelial neoplasia (HGIN), and 55 (0.35%) with EC, respectively. The overall prevalence of depression symptoms of participants was 4.16% (health: 4.63%, esophagitis: 2.99%, LGIN: 2.99%, HGIN: 5.73%, and EC: 9.09%). Multiple logistic regression analyses revealed that the unadjusted OR (95% CI) between depression and each esophageal pathology grades were esophagitis 0.93 (0.92-0.95), LGIN 0.97 (0.94-0.99), HGIN 1.05 (1.00-1.10), and EC 1.04 (0.97-1.14), respectively. However, after adjustment for potential confounders (age, gender, region, alcohol consumption, BMI), no statistically significant associations between depression and EC (adjusted OR = 1.10, 0.99-1.21) and esophageal lesions (esophagitis: adjusted OR = 1.02, 0.99-1.04; LGIN: adjusted OR = 0.98, 0.95-1.01; HGIN: adjusted OR = 1.04, 0.98-1.11) were observed in this study. Conclusions No significant association was observed between depression and EC in the study. Future prospective cohort studies are needed to verify this preliminary finding.