Hollow mesoporous zirconia nanocapsules (hm-ZrO2) with a hollow core/porous shell structure are demonstrated as effective vehicles for anti-cancer drug delivery. While the highly porous feature of the shell allows the drug, doxorubicin(DOX), to easily pass through between the inner void space and surrounding environment of the particles, the void space in the core endows the nanocapsules with high drug loading capacity. The larger the inner hollow diameter, the higher their DOX loading capacity. A loading of 102% related to the weight of hm-ZrO2 is achieved by the nanocapsules with an inner diameter of 385 nm. Due to their pH-dependent charge nature, hm-ZrO2 loaded DOX exhibit pH-dependent drug releasing kinetics. A lower pH offers a faster DOX release rate from hm-ZrO2. Such a property makes the loaded DOX easily release from the nanocapsules when up-taken by living cells. Although the flow cytometry reveals more uptake of hm-ZrO2 particles by normal cells, hm-ZrO2 loaded DOX release more drugs in cancer cells than in normal cells, leading to more cytotoxicity toward tumor cells and less cytotoxicity to healthy cells than free DOX.