MicroRNAs (miRNAs) are critical for cancer development and progression. Elucidating the underlying mechanism of miRNAs in carcinogenesis may lead to novel diagnostic and therapeutic strategies for malignancy. In this study, we found that miR-511 expression was markedly downregulated in hepatocellular carcinoma (HCC) cell lines and tissues. Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was identified as a direct target of miR-511 and miR-511 expression inversely correlated with PIK3R3 mRNA expression in clinical HCC tissues. We further demonstrated that miR-511 suppressed HCC cell proliferation, migration, and invasion by repressing PIK3R3 expression. Investigations of possible mechanisms underlying these results revealed that miR-511 inhibited the phosphorylation of AKT and mTOR, which are key participants in the AKT/mTOR pathway. Taken together, our findings provide new insights into tumor suppression by miR-511 by negatively regulating the PIK3R3/AKT/mTOR signaling pathway.