Targeting EGFR and HER-2 is an essential direction for cancer treatment. Here, a series of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure was designed and synthesized to serve as EGFR/HER-2 dual-target inhibitors. The kinase assays verified that target compounds could inhibit the kinase activity of EGFR and HER-2 selectively. The results of CCK-8 and 3D cell viability assays confirmed that target compounds had excellent anti-proliferation ability against breast cancer cells (MCF-7 and SK-BR-3) and lung cancer cells (A549 and H1975), particularly against SK-BR-3 cells, while the inhibitory effect on healthy breast cells (MCF-10A) and lung cells (Beas-2B) was weak. Among them, the hit compound YH-9 binded to EGFR and HER-2 stably in molecular dynamics studies. Further studies found that?YH-9?could induce the release of cytochrome c and inhibit proliferation by promoting ROS expression in SK-BR-3 cells. Moreover,?YH-9?could diminish the secretion of VEGF and bFGF factors in SK-BR-3 cells, then inhibited tube formation and angiogenesis. Notably,?YH-9?could effectively inhibit breast cancer growth and angiogenesis with little toxicity in the SK-BR-3 cell xenograft model. Taken together,?in vitro?and?in vivo?results revealed that YH-9 had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth and angiogenesis.