Chemotherapy is the most common and powerful cancer treatment. Although the nasty side effects seriously influence the clinical practice, no better ways can displace it. Therefore, searching for safe and effective strategies designed to ameliorate chemotherapy-induced toxicity has become an urgent issue in cancer research area. In clinical, a medicinal and edible formula YH0618 showed the effects of reducing the DOX-induced toxicity, especially improving alopecia, nail discoloration, skin hyperpigmentation and fatigue. This study was to investigate the role and mechanism of YH0618 in ameliorating DOX-induced toxicity by in vitro and in vivo experiments. YH0618 selectively attenuated DOX-induced growth inhibition and apoptosis in human normal liver L02 cells and kidney HEK-293 cells, and simultaneously potentiated the anti-cancer effect of DOX in breast cancer MCF-7 and MDA-MB-231 cells by apoptosis pathways. Western blotting results revealed that YH0618 attenuated DOX-induced apoptosis in normal liver and kidney cells through FOXO4-mediated mitochondria-dependent mechanism. Animal experiments demonstrated that, YH0618 did not interfere in DOX-induced reduction in tumor volume and significantly improved DOX-induced hair loss and the increase of alanine aminotransferase (ALT). Histological characteristics showed that YH0618 attenuated DOX-induced heart, liver and kidney damage. The study may shed light on the potential application of YH0618 as a novel medicinal food against chemotherapy-induced toxicity.