Tanshinone IIA is a potent anti-tumor agent; however, its therapeutic applications have been hindered by its intrinsic poor solubility and short half-life. Herein we report the design and synthesis of amphiphilic PEG-poly(amino acid)s (PPAAs), which were used as a nanocarrier to encapsulate tanshinone IIA. PPAA-encapsulated tanshinone IIA formed defined nanoparticles and effectively arrested the growth of the hepatoma tumor in MHCC97-H hepatoma-bearing mice, which has therefore significantly increased their survival time. Moreover, these tanshinone-loaded nanoparticles are also capable of suppressing hepatic tumor cell migration and metastasis. In all cases, they significantly improve efficacy compared to tanshinone alone. Our results show that tanshinone IIA encapsulated by PPAAs is a potential novel nanomedicine for the treatment of hepatoma. Furthermore, this use is only a proof of concept, and PPAAs can be used as a potential drug delivery system for a much broader array of hydrophobic drugs.