Furanodiene is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anticancer effects in various types of cancer cell lines. In this study, we have successfully established zebrafish xenografts with 5 various human cancer cell lines; and validated these models with anti-cancer drugs used clinically for treating human cancer patients. We found that Furanodiene was therapeutically effective for human JF 305 pancreatic cancer cells and MCF-7 breast cancer cells xenotranplanted into zebrafish. Furanodiene showed a markedly synergistic anti-cancer effect when used in combination with 5-FU (5-Fluorouracil) for both human breast cancer MDA-MB-231 cells and human liver cancer BEL-7402 cells xenotransplanted into zebrafish. Unexpectedly, Furanodiene reversed multiple drug resistance in the zebrafish xenotransplanted with cis-Platinum-resistant human non-small cell lung cancer cells and Adriamycin-resistant human breast cancer cells. Furanodiene played its anti-cancer effects through anti-angiogenesis and inducing ROS production, DNA strand breaks and apoptosis. Furanodiene suppresseed efflux transporter Pgp (P-glycoprotein) function and reduced Pgp protein level, but no effect on Pgp related gene (MDR1) expression. These results suggest sensitizition and synergistic anti-cancer effects of Furanodiene that is worthy of a further investigation.