LiNi0.6Mn0.2Co0.2O2 is a promising cathode material with a high capacity for Li-ion batteries. However, the rapid capacity degradation in the high-voltage cycles constrain their further applications. Accordingly, the performances of LiNi0.6Mn0.2Co0.2O2 have been systematically investigated using various microstructural characterizations as well as electrochemical analyses to explore its degradation mechanism. Our results indicate that the capacity decay of LiNi0.6Mn0.2Co0.2O2 strongly depends on the charge cut-off voltage. For the cell that is cycled at 4.2 or 4.5 V, the degradation mechanism is primarily due to transformation from layered to rock salt structure on the particle surface, increasing the charge transfer impedance. For the cell that is cycled at 4.8 V, another two reasons should be considered. The irreversible structural change in the bulk lattice of LiNi0.6Mn0.2Co0.2O2 during the high-degree delithiation process eventually disintegrates the secondary particles, resulting in the poor electrical contact between particles. Another one is that the insulating surface film which is generated on the surface of particles after cycling at 4.8 V increases the interfacial impedance of LiNi0.6Mn0.2Co0.2O2. All these factors contribute to the overall capacity degradation at high voltages.