Annexin A5 has been found to act as an oncogenic protein in a variety of cancers. However, its specific biological role and mechanism in renal cell cancer (RCC) remains unknown. Quantitative Real-time PCR and western blotting were used to evaluate the mRNA and protein expression level of Annexin A5 in human RCC cell lines and tissues. Immunohistochemistry was adopted to measure the Annexin A5 expression in 123 cases of RCC tissues. Survival analysis was performed to explore the association between Annexin A5 expression and the prognosis of RCC. The effect of Annexin A5 on RCC growth and metastasis was studied in vitro and in vivo. Annexin A5 was frequently highly expressed in both human RCC cells and tissues. High Annexin A5 expression was associated with higher clinical stage and histological grade. In addition, Annexin A5 might be used as a predictive factor for the prognosis of RCC. Further research suggested that upregulated Annexin A5 in RCC cells could significantly promote tumor cell proliferation, migration and invasion in vitro. Subcutaneous xenograft tumor model displayed that knockdown of Annexin A5 could impede tumorigenesis in vivo. Moreover, mechanism study exhibited that Annexin A5 could activate PI3K/Akt/mTOR signaling pathway, promote epithelial-mesenchymal transition (EMT) and the expression of MMP2 and MMP9. Annexin A5 may be a potential prognostic biomarker in RCC and promotes proliferation, migration and invasion of RCC cells via activating PI3K/Akt/mTOR signaling pathway and regulating EMT process and MMP expression.