Background <p>Esophageal cancer (EC) is the ninth most common cancer globally. Circular RNAs (circRNAs), including hsa_circ_0036722, are important in various cancers, but their specific role in EC remains unclear. Therefore, this study investigates the roles of hsa_circ_0036722 in EC.</p> Methods <p>We analyzed circRNAs sequencing from Gene Expression Omnibus (GEO). On the other hand, analyzed miRNAs and mRNAs sequencing related to EC from The Cancer Genome Atlas (TCGA). Then, the hsa_circ_0036722/hsa-mir-503-5p/PDCD4 axis was identified using online tools for detecting circRNA-associated miRNAs and target mRNAs. Gene expression levels in 20 EC tissue pairs were assessed using RT-qPCR, while PDCD4 protein expression was evaluated by Western blot. A receiver operating characteristic (ROC) analysis was performed to evaluate their diagnostic potential.</p> Results <p>RT-qPCR results demonstrated decreased expression of hsa_circ_0036722 and PDCD4, alongside increased hsa-miR-503-5p expression in EC tissues. A reduction in PDCD4 protein expression was also noted. Correlations showed that hsa_circ_0036722 and PDCD4 expressions were positively correlated, while hsa_circ_0036722 and hsa-miR-503-5p were negatively correlated. In addition, a significant negative correlation was observed between hsa-miR-503-5p and PDCD4 expression. Elevated levels of hsa-miR-503-5p were detected in early stages of EC. The ROC curve reflected a significant area under the curve for the axis genes.</p> Conclusion <p>This study identified a novel regulatory axis, hsa_circ_0036722/hsa-mir-503-5p/PDCD4, for regulating EC, which may be a potential target for treating patients with this cancer.</p>