The dysfunction of histone deacetylase (HDACs) is closely related to tumorigenesis and development, which has been emerged as an attractive drug design target for cancer therapy. In the present study, we designed and synthesized a series of novel HDAC inhibitors using a substituted quinazoline as the capping group and attaching 3, 5-dimethylbenyl as a potential metabolic site protector. 23g and 23h were demonstrated potent HDAC inhibitory activities and anti-proliferative effects against MDA-MB-231 cells. In addition, 23g and 23h both could significantly increase the acetylation level of intracellular proteins, especially in α-Tubulin and HSP90. 23g and 23h displayed a slight different anti-tumor mechanism, 23g mainly induced apoptosis while 23h induced obviously ER-Stress. Furthermore, 23g and 23h both induced autophagy and migration inhibition. In pharmacokinetics assay, 23g showed a significant improvement of pharmacokinetic profile for oral administration. Additionally, 23g presented more potent anti-proliferation and anti-migration activity than SAHA in zebrafish MDA-MB-231 cell line-derived xenograft model. Together, these results demonstrate that 23g is a novel oral HDAC inhibitor with a potential capacity of treating breast cancer.