A series of novel ligustrazine-chalcone hybrids were synthesized and evaluated for their in vitro and in vivo antitumor activities. The results showed that most of these compounds exhibited significant in vitro cytotoxicity against MDA-MB-231, MCF-7, A549 and HepG2 cell lines with IC<sub>50</sub> values as low as sub-micromole. Among them, compounds 6c and 6f possessed better comprehensive characteristics for the antiproliferation effects on both MDA-MB-231 (IC<sub>50</sub>: 6c, 1.60 ± 0.21 μM; 6f, 1.67 ± 1.25 μM) and MCF-7 (IC<sub>50</sub>: 6c, 1.41 ± 0.23 μM; 6f, 1.54 ± 0.30 μM). They also exhibited the potent colony-formation inhibitory abilities on above two cell lines in both concentration and time dependent manners, as well as the significantly suppression capabilities against the migration of such cell lines in a concentration dependent manner by wound-healing assay. Of note, compound 6c could significantly induce the apoptosis of MDA-MB-231 cells in a concentration dependent manner and inhibited the transformation of the growth cycle of MDA-MB-231 cells and blocked the cell growth cycle in G0/G1 phase. Moreover, the in vivo antiproliferation assay of compound 6c on TNBC model indicated such compound had a remarkable potency against tumor growth with a widely safety window. Further immunohistochemistry analysis illustrated that compound 6c was provided with a potent capacity to significantly reduce the Ki-67 positive rate in a dose dependent manner. All the results suggested that these hybrids presented both in vitro and in vivo proliferation inhibition potency against breast cancer and further development with good therapeutic potential should be of great interest.