Multidrug resistance (MDR) has become one of the most intractable problems in clinics as it would cause failure in chemotherapy. In this study, we demonstrated that a nanoscale self-assembled nanomedicine, which almost consisted of a pure chemo-drug, could efficiently overcome MDR. Celastrol (CST) was directly assembled into a discrete nanomedicine by precipitation, and then CST nanoparticles (CNPs) inhibited drug efflux pumps by activating HSF-1 expression and promoting HSF-1 translocation into nucleus to suppress the Pgp expression. The more drug accumulated in cells could activate apoptosis signals simultaneously and realize drug resistance reversal. CNPs significantly increased the level of ROS to regulate ERK/JNK signaling, which would further induce resistant cell apoptosis. The tandem apoptosis strategy used the same concentration of CST but achieved a higher antitumor effect. Overall, our study provides a new translational and alternative strategy using conventional natural products to overcome MDR with high efficacy.