The authors investigate the crystallinity and surface effects on Young’s modulus of cupric oxide (CuO) nanowires by performing three-point bend test using atomic force microscopy. Young’s modulus of the nanowires obtained ranges from 70 to 300 GPa and is dependent on two factors. Firstly, it depends on whether the nanowire is mono- or polycrystalline, as indicated by the absence or presence of an amorphous surface layer. Second, the modulus increases with decreasing diameter for both types of nanowires. Combined with transmission electron microscopy and computational simulation studies, the nanostructure-mechanical property relationship of CuO nanowires is elucidated.