Based on the antisolvent and electrostatic deposition methods, we fabricated zein/hyaluronic acid core-shell nanoparticles loaded with honokiol (HA-Zein-HNK), which could target delivery and enhance the therapeutic effect of the HNK. The prepared nanoparticles were found to have a mean size of 210.4 nm and negative surface charge. The HA-Zein-HNK nanoparticles exhibited improved antiproliferative and pro-apoptotic activities against 4T1 cells. Of note, the wound healing and transwell assessments indicated that the migration and invasion of 4T1 cells were markedly weakened by HA-Zein-HNK. Mechanistic insights revealed that HA-Zein-HNK downregulated the expressions of Vimentin and upregulated the expressions of E-cadherin. More importantly, an in vivo tissue distribution study demonstrated the excellent tumor target ability of HA-Zein. And these results correspond with the superior therapeutic efficacy of HA-Zein-HNK in 4T1 tumor bearing mice. In conclusion, we believe that HA-Zein nanoparticles may be served as a promising HNK delivery carrier for metastatic breast cancer therapy.