Renal cell carcinoma (RCC) is one of the most common urinary malignancies with a high rate of morbidity. MicroRNAs (miRNAs) have been shown to be critical post?transcriptional regulators in tumorigenesis. The present study aimed to investigate the effect of miRNA (miR)?539 on the proliferation and apoptosis of RCC. The expression of miR?539 and high mobility group AT?hook 2(HMGA2) were examined in clinical RCC specimens. The 786?O RCC cell line was also used and was transfected with miR?539 mimics or inhibitors. The correlation between miR?539 and HMGA2 was confirmed using a luciferase reporter assay. Cell viability and apoptosis were detected using MTT and flow cytometry assays. The protein levels of HMGA2, AKT, phosphorylated (p)?AKT, mammalian target of rapamycin (mTOR) and p?mTOR were analyzed using western blot analysis. The results revealed that miR?539 was negatively correlated with the expression of HMGA2 in clinical RCC specimens. Further experiments identified HMGA2 as a direct target of miR?539. The overexpression of miR?539 downregulated the expression of HMGA2, reduced cell proliferation and promoted cell apoptosis, whereas the knockdown of miR?539 led to the opposite results. miR?539 also suppressed the phosphorylation of AKT and mTOR, without altering the levels of total AKT and mTOR. Taken together, the results of the present study indicated that miR?539 negatively regulated the expression of HMGA2 in clinical specimens and in?vitro. miR539 inhibited cell proliferation and induced apoptosis in RCC cells. This regulatory effect of miR?539 may be associated with the AKT signaling pathway. Therefore, miR?539 may be used as a biomarker for predicting the progression of RCC.