Most of the therapeutic strategies to counteract cancer imply killing of malignant cells. The most exploited cell death mechanism in cancer therapies is apoptosis, but recently, a lot of papers report that other mechanisms, mainly autophagy, could represent a new line of attack in the fight against cancer. One of the limitations for the effectiveness of the approved clinical treatments is the phenomenon of multidrug resistance (MDR) which enables the cancer cells to develop resistance to therapy, especially for chemotherapy. The MDR mechanisms include (a) decreased uptake of drug, (b) reduced intracellular drug concentration by efflux pumps, (c) altered cell cycle checkpoints, (d) altered drug targets, (e) increased metabolism of drugs, (f) induced emergency response genes to impair apoptotic pathway, and (g) altered drug detoxification. Great efforts have been made to reverse MDR. Currently, autophagy and nanosized drug delivery systems (DDSs) belonging to nanomaterials (NMs) provide alternative strategies to circumvent MDR. Nanosized DDSs are very promising tools to accumulate chemotherapeutics at targeting sites and control temporal and spatial drug release into tumor cells. On the other hand, autophagy could overrule drug resistance upon its activation by ensuring cell death via switching its prosurvival role to a prodeath one or by mediating the occurrence of cell death, i.e., apoptosis or necrosis. Likewise, the autophagy inhibition could counteract MDR by sensitizing the cells to anticancer molecules, i.e., Src family tyrosine kinase (SFK) inhibitors or 5-fluorouracil. Noteworthy, autophagy has been recently indicated to be a common cellular response to NMs, corroborating the fascinating idea of the exploitation of NM-induced autophagy in nanomedicine therapy. This review focuses on recently published literature about the relationship between MDR reversal and NMs or autophagy pointing to hypothesize a pivotal role of autophagy modulation induced by NMs in counteracting MDR.