Copper oxide nanoparticles were prepared by the solvothermal method, and characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and nitrogen adsorption-desorption measurements. The as-prepared CuO nanoparticles functionalized QCM resonators were fabricated and explored for HCN sensing under varied humidity conditions. When the humidity of air containing HCN is the same as that of environmental air, a characteristic positive frequency shift of CuO nanoparticles functionalized QCM resonator is always observed towards HCN because of a reversible surface redox reaction between CuO and HCN. The sensitivity of CuO nanoparticles functionalized QCM resonators increases with increase of relative humidity in the range of 9-51%. These results provide an important guidance for further developing HCN gas sensors towards practical applications.