Hepatocellular carcinoma (HCC) is one of most common causes of cancer death worldwide. MicroRNA (miRNA) replacement gene therapy is a novel approach for HCC management. MiR-218 is a promising tumor suppressor miRNA that is down-regulated in HCC. Here, our aim was the targeted delivery of miR-218 expressing DNA plasmid (pmiR-218) to suppress HCC in vitro and in vivo. Hyperbranched polyamidoamine was synthesized via simple and economically one-pot reaction followed by decoration with lactobionic acid (LA-PAMAM) to selectively deliver and restore miR-218 expression in HCC. In vitro cytotoxicity investigations revealed the high biocompatibility of LA-PAMAM. Furthermore, decoration of hyperbranched polymer with LA moieties enabled LA-PAMAM to deliver pmiR-218 more efficiently to HepG2 cells compared to both PMAMA and naked pmiR-218. Such efficient delivery of miR-218 resulted in suppression of HepG2 proliferation and down-regulation of its oncogenic HOXA1 target. In vivo, LA-PAMAM/pmiR-218 treatment of HCC induced by DEN and CCl₄ in mice leads to an obvious decrease in the number and size of HCC nodules. In addition, LA-PAMAM/pmiR-218 significantly improved the liver histological features, as well as down-regulated the HOXA1 in liver tissue. In conclusion, this study showed the potential of LA-PAMAM carrier for the targeted delivery of tumor suppressor miR-218 as a therapeutic candidate for HCC.