In this investigation, the size-scale in mechanical properties of individual [0001] ZnO nanowires and the correlation with atomic-scale arrangements were explored via in situ high-resolution transmission electron microscopy (TEM) equipped with atomic force microscopy (AFM) and nanoindentation (NI) systems. The Young's modulus was determined to be size-scale-dependent for nanowires with diameter, d, in the range of 40 nm ≤ d ≤ 110 nm, and reached the maximum of ∼ 249 GPa for d = 40 nm. However, this phenomenon was not observed for nanowires in the range of 200 nm ≤ d ≤ 400 nm, where an average constant Young's modulus of ∼ 147.3 GPa was detected, close to the modulus value of bulk ZnO. A size-scale dependence in the failure of nanowires was also observed. The thick ZnO nanowires (d ≥ 200 nm) were brittle, while the thin nanowires (d ≤ 110 nm) were highly flexible. The diameter effect and enhanced Young's modulus observed in thin ZnO nanowires are due to the combined effects of surface relaxation and long-range interactions present in ionic crystals, which leads to much stiffer surfaces than bulk wires. The brittle failure in thicker ZnO wires was initiated from the outermost layer, where the maximum tensile stress operates and propagates along the (0001) planes. After a number of loading and unloading cycles, the highly compressed region of the thinner nanowires was transformed from a crystalline to an amorphous phase, and the region near the neutral zone was converted into a mixture of disordered atomic planes and bent lattice fringes as revealed by high-resolution images.