Adriamycin is a first-line chemotherapy agent against cancer， but the development of resistance has become a major problem. Although autophagy is considered to be an adaptive survival response in response to chemotherapy and may be associated with chemoresistance， its inducer and the underlying molecular mechanisms remain unclear. Here， we demonstrate that adriamycin up-regulates the both levels of TRPC5 and autophagy， and the increase in autophagy is mediated by TRPC5 in breast cancer cells. Blockade of TRPC5 or autophagy increased the sensitivity to chemotherapy in vitro and in vivo. Notably， we revealed a positive correlation between TRPC5 and the autophagy-associated protein LC3 in paired patients with or without anthracycline-taxane-based chemotherapy. Furthermore， pharmacological inhibition and gene-silencing showed that the cytoprotective autophagy mediated by TRPC5 during adriamycin treatment is dependent on the CaMKKβ/AMPKα/mTOR pathway. Moreover， adriamycin-resistant MCF-7/ADM cells maintained a high basal level of autophagy， and silencing of TRPC5 and inhibition of autophagy counteracted the resistance to adriamycin. Thus， our results revealed a novel role of TRPC5 as an inducer of autophagy， and this suggests a novel mechanism of drug resistance in chemotherapy for breast cancer.