The C-X-C chemokine receptor 4 (CXCR4) has been reported to be involved in several cancer related processes. The current study was designed to investigate the role of CXCR4 in human kidney cancer and to unveil the underlying molecular mechanisms. The results showed the expression of CXCR4 to be significantly (P<0.05) upregulated in human renal cancer tissues and cell lines. Silencing of CXCR4 lead to a significant (P<0.05) decline of cell proliferation and colony formation of the Caki-1 and A498 kidney cancer cells. Moreover, the migration and invasion of the Caki-1 and A498 cells was also significantly (P<0.05) inhibited upon CXCR4 silencing. TargetScan analysis and dual luciferase assay revealed that CXCR4 interacts with microRNA-139 (miR-139). The expression of miR-139 was found to be significantly (P<0.05) downregulated in human kidney cancer cells lines. Overexpression of miR-139 caused post-transcriptional suppression of CXCR4 expression and significant (P<0.05) inhibition of the Caki-1 and A498 cell proliferation. Nonetheless, CXCR4 overexpression could nullify the inhibitory effects of miR-139 on the proliferation of Caki-1 and A498 cells. Taken together, the results revealed that CXCR/miR-139 axis regulates the proliferation, migration, and invasion of human kidney cancer cells and may act as a therapeutic target.