In modern biology, one of the major topics of importance is progress in anti-cancer drugs with specific targets. The angiopreventive and <i>in vitro</i> tumor inhibition activities of novel synthetic benzophenone analogs have been investigated intensively and explored in a very systematic way. Novel benzophenone analogs (<b>9a-d</b> and <b>10a-d</b>) substituted with methyl, chloro and fluoro groups at different positions on an identical chemical backbone and incorporating variations in the number of substituents have been synthesized in a multistep process and characterized. In this study, we further evaluate the newly synthesized compounds for their cytotoxic and anti-proliferative effects against A549, HeLa and MCF-7 cells. The potent lead compound was further assessed for anti-angiogenic effects. Through the structure-activity relationship, we found that an increase in the number of methyl, chloro and fluoro groups in a benzophenone ring on compound <b>9d</b> resulted in higher potency compared to other compounds. Tumor inhibition was notably promoted, and this was reflected in effects on neovessel formation in <i>in vivo</i> systems, such as the CAM. Compound <b>9d</b> interacts with rVEGF through hydrogen bonds <i>in silico</i>, thereby down-regulating the expression of VEGF in angiogenesis. From our investigation, it is suggested on the basis of clonogenesis and cell migration assays that compound <b>9d</b> has the potency to exhibit prolonged activity against cancer progression, through cell cycle arrest at the G2/M phase. In addition, compound <b>9d</b> inhibits A549 cells through caspase-activated DNase-mediated apoptosis.