Persistent activation of IGF1R/mTOR signaling pathway plays crucial role in the development of hepatocellular carcinoma (HCC). Therefore, our goal was to elucidate microRNAs (miRNAs) targeting IGF1R/mTOR and the therapeutic potential of single or dual miRNA on HCC development. In this study, we found that miR-497 and miR-99a that target the 3'-UTR of both IGF1R and mTOR were down-regulated in HCC human tissues and cell lines. Functional assay revealed that ectopic expression of miR-497 or miR-99a in HCC cells resulted in a significant inhibition on tumor growth and invasiveness in vitro and tumor development in vivo via repressing the expression of IGF1R and mTOR. Such inhibitory effect on tumor growth is reversed by application of IGF1 ((IGF1R ligand) or MHY1485 (mTOR agonist) in vitro. Furthermore, we found that simultaneous over-expression of both miR-497 and miR-99a exhibited much stronger inhibitory effects on tumor growth than their individual effect, which is still correlated with significantly stronger repression of IGF1R and mTOR. Overall, our results suggest that miR-497 and miR-99a both function as tumor-suppressive miRNAs by suppressing IGF1R/mTOR signaling pathway. The synergistic actions of these two miRNAs partly correlated with IGF1R and mTOR levels, which may represent new strategies for the molecular treatment of HCC.