Overexpression of apoptotic factors in the inner ear is generally proven to induce ototoxicity. This has aroused research interest in various antiapoptotic drugs, the most representative of which is curcumin (CUR). In this study, two nanoformulations of CUR were developed with sustained-release behavior to improve their protective effects against ototoxic hearing loss (HL), which were the nanoparticles of CUR-loaded poly(lactic acid-glycolic acid) (CUR-PLGA NPs) and CUR-loaded chitosan-coated PLGA NPs (CUR-CS/PLGA NPs). The obtained results revealed that both CUR-NPs provided otoprotection in vitro and in vivo, and their effective doses in guinea pigs were much less than that of dexamethasone, which was clinically used to treat HL. Moreover, relative to CUR and CUR-PLGA NPs, CUR-CS/PLGA NPs exhibited the highest accumulation in HEI-OC1 cells and guinea pigs' cochlea. In pharmacodynamic experiments, the optimal administration timing was investigated, and CUR-CS/PLGA NPs showed sustained efficacy and the best hearing improvement at all tested sound frequencies. Lastly, the protective effect of CUR nanoformulations was further validated via inhibition of Caspase-3 and Bax activation, thereby reducing the concentration of reactive oxygen species and protecting mitochondrial integrity in hair cells. Collectively, CUR-CS/PLGA NPs demonstrated potent and lasting effects against ototoxic HL, making our novel formulation a promising candidate for the alleviation of sensorineural HL.