MLN8237, a specific inhibitor of Aurora-A kinase, is proved to be a potential treatment strategy for hepatocellular carcinoma (HCC). Nanogels improve the efficacy of doxorubicin. Therefore, this study aims to investigate the increase in the effect of nanogels on MLN8237 in inhibiting HCC. Doxorubicin or MLN8237 was used as an anti-tumor drug models which were packaged by organic solvent volatilization method to obtain the doxorubicin-loaded nanogel and the MLN8237-loaded nanogel. Subsequently, CCK8 assay, cell cycle assay, apoptosis assay, real-time PCR, western blotting assay and animal experiments were used to detect the effects of MLN8237 nanogel on the proliferation, cell cycle, apoptosis, tumor growth, mRNA and protein levels of aurora-A and PUMA, and AKT phosphorylation levels in HCC cell lines. The results show that the nanogels can realize pH-regulated hydrophobicity reversal, have certain stability, and can realize lysosomal escape. Moreover, the MLN8237-loaded nanogel has a stronger ability to inhibit HCC cell proliferation, block cell cycle, promote apoptosis and inhibit tumor growth than free MLN8237 by suppressing aurora-A and AKT phosphorylation. In short, nanogel can enhance the efficacy of MLN8237.