In this work, quartz crystal microbalance (QCM) sensors for detection of trace hydrogen cyanide (HCN) gas were developed based on nanostructural (flower-like, boat-like, ellipsoid-like, plate-like) CuO. Responses of all the sensors to HCN were found to be in an opposite direction as compared with other common volatile substances, offering excellent selectivity for HCN detection. The sensitivity of these sensors is dependent on the morphology of CuO nanostructures, among which the plate-like CuO has the highest sensitivity (2.26 Hz/μg). Comparison of the specific surface areas of CuO nanostructures shows that CuO of higher surface area (9.3 m(2)/g) is more sensitive than that of lower surface area (1.5 m(2)/g), indicating that the specific surface area of these CuO nanostructures plays an important role in the sensitivity of related sensors. On the basis of experimental results, a sensing mechanism was proposed in which a surface redox reaction occurs between CuO and Cu(2)O on the CuO nanostructures reversibly upon contact with HCN and air, respectively. The CuO-functionalized QCM sensors are considered to be a promising candidate for trace HCN gas detection in practical applications.