Autophagy induction is responsible for the chemoresistance of histone deacetylase (HDAC) inhibitors. The combination of HDAC inhibitors with autophagy inhibitors has been considered a new strategy for treating solid tumors. However, codelivery systems capable of transporting these two kinds of drugs with different physicochemical properties and the simultaneous release of drugs remain elusive. In this study, hollow zirconium dioxide (ZrO) nanoshells were synthesized to encapsulate both the autophagy inhibitor chloroquine (CQ) and the HDAC inhibitor vorinostat (Vor) for effective combinational cancer therapy. The ZrO nanoshells showed high loading capacities for both CQ and Vor due to the high affinity of ZrO for the phosphate and hydroxamic acid groups of the drugs, and the drug-loaded ZrO nanoshells exhibited a controlled release profile. The intrinsic autophagy inhibitory effect of the ZrO nanoshells enhanced the effect of either the single drug (CQ or Vor) or the combination of these two drugs. The codelivery system enhanced the autophagy inhibition and hyperacetylation level in the cells compared with free drugs, resulting in a superior antitumor effect in 4T1 tumor-bearing mice. Taken together, the multifunctional ZrO nanoshells hold great potential for the codelivery of HDAC and autophagy inhibitors for solid tumors therapy.