Many anti-cancer drugs are used in the clinic; however, little is known about their efficacy in circulating tumor cells (CTCs). In this study, we investigated whether the pulsatile fluidic shear stress (SS) in human arteries can affect the efficacy of anti-cancer drugs. Cancer cells were circulated in our microfluidic circulatory system, and their responses to drug and SS treatments were determined. The results showed that fluidic SS significantly increased the potency of the reactive oxygen species (ROS)-generating drugs doxorubicin (DOX) and cisplatin but had little effect on the non-ROS-generating drugs Taxol and etoposide. Co-treatment with SS and ROS-generating drugs dramatically elevated ROS levels in CTCs, while adding antioxidants abolished the apoptotic effects of DOX and cisplatin. More importantly, the synergistic killing effects of SS and DOX or cisplatin were confirmed in circulated lung, breast, and cervical cancer cells, some of which have a strong metastatic ability. These new findings suggest that ROS-generating drugs are more potent than non-ROS-generating drugs for destroying CTCs under pulsatile fluidic conditions. This new information is highly valuable for developing novel therapies to abolish CTCs in the circulation and prevent metastasis.