High-Ni NCM (LiNixCoyMnzO2) has been widely adopted as a promising solution for enhancing the energy density of lithium-ion batteries (LIBs) owing to its high theoretical specific capacity and wide operating voltage. Because of the high oxidation stability, a carbonate electrolyte containing LiPF6 salt is employed in such a battery system; however, LiPF6 reacts with the residual moisture, which remains even after thorough drying processes, to produce detrimental hydrofluoric acid (HF) promoting the significant structural degradation of high-Ni NCM. Herein, a moisture-responsive dehumidifying separator incorporating an oxygen-deficient TiO2–x nanolayer was developed to mitigate the water-induced electrochemical degradation of LIBs paired with high-Ni NCM cathodes, thereby stabilizing the electrochemical performance even under highly humid conditions. Owing to the advantageous characteristics of the oxygen-deficient TiO2–x, which spontaneously transforms into TiO2 by reacting with moisture, LIBs employing the TiO2–x/PE separator achieved a stable electrochemical performance even under extreme conditions of high H2O concentration and high cutoff voltage by suppressing the H2O-induced electrochemical deterioration. This dehumidifying separator would expedite the commercialization of the LIBs using high-Ni NCM and LiPF6-based electrolyte by mitigating the electrochemical degradation of electrodes caused by residual H2O.