Chemotherapy is a primary approach in cancer treatment after routine surgery. However, chemo-resistance and side effects tend to occur with chemotherapy in clinic, resulting in poor prognosis and recurrence. Nowadays, Chinese medicine may shed light on design of new therapeutic modes to overcome chemo-resistance. Rhizoma curcumae, known as Ezhu (Chinese), a commonly used traditional Chinese medicinal herb, is the dried rhizome of the following three species: Curcuma phaeocaulis, Curcuma kwangsiensis and Curcuma wenyujin. The major active constituents comprise curcuminoids and terpenoids. Furanodiene, as a heat-sensitive sesquiterpene, is isolated from the essential oil of Rhizoma Curcumae. Even though growing evidence claimed that Rhizoma Curcumae possesses anticancer activities in various types of cancer, its bioactive components as well as the underlying mechanisms against chemo-resistant cancer are not clear. Previous studies also proved that furanodiene could enhance growth inhibition of steroidal agent in ERα-positive breast cancer cells. However, anti-cancer effects of furanodiene in combination with the non-steroidal agents on cell viability and cell metastasis in breast cancer cells have not yet been investigated. Therefore, the present study aims to explore the potential effect of Rhizoma Curcumae on breast cancer. Our study demonstrates that essential oil, furanodienone, and furanodiene are not specific inhibitors of ABC transporters, but display a powerful inhibitory effect on viability of doxorubicin-resistant MCF-7 cells. Furthermore, furanodiene preferentially causes apoptosis by interfering with the intrinsic/extrinsic pathways, and also suppresses proliferation by arresting cell cycle in doxorubicin-resistant iv MCF-7 cells. Moreover, furanodiene noticeably induces AMPK phosphorylation, which suggests that furanodiene reduces mitochondrial function by way of AMPK activation in doxorubicin-resistant and -sensitive MCF-7 cells. Accordingly, we presume that furanodiene could be used to overcome chemo-resistance via targeting energy sensor AMPK. Finally, furanodiene enhances growth inhibitory effect of doxorubicin in ERα-negative and doxorubicin-sensitive MDA-MB-231 cells through inducing apoptosis in mitochondria-caspases-dependent and ROS-independent manners, and blocks doxorubicin-induced cell invasion and migration through regulation of Integrin αV, FAK/Src/Paxillin, PI3K/Akt, β-catenin, and MMP-9 signaling pathways. Taken together, our findings fill the gap of the researches on the anti-cancer effects of Rhizoma Curcumae in chemo-resistant cancer cells. These observations also prompt that Rhizoma Curcumae can be developed as a promising natural plant for cancer adjuvant therapy in the future.