Esophageal cancer (EC) is considered one of the most lethal cancers in human beings, and multiple miRNAs have been investigated to be involved in EC development by targeting their target genes. However, the function and related mechanism of miRNA-497 on EC tumorigenesis remain uncertain. This study first demonstrated that the expression levels of miR-497 in esophageal cancer specimens and cells were down-regulated. Forced expression of miR-497 inhibited cell proliferation, tube formation and migration in EC cells. To further investigate the potential molecular mechanism of miR-497 suppression in regulating EC, we found that miR-497 directly binds to the 3'-untranslational region of QKI, miR-497 overexpression suppressed QKI expression. We further found that overexpression of miR-497 enhanced the effect of chemotherapy in EC cell lines, and prevented the tumor growth of EC in vivo. Our findings indicated that miR-497 suppression increased QKI expression and therapeutic resistance of esophageal cancer, which is likely to be a biomarker of EC progression and potential therapeutic target.