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A microstructured cover flow mixer equipped with two cyclone structures was used for stable continuous hydrothermal synthesis of ZnO nanoparticles from Zn(NO3)2 and NaOH aqueous solutions in supercritical water. The effects of the NaOH/Zn(NO3)2 ratio, Zn(NO3)2 molality, and flow rate on Zn conversion, crystal structure, particle size, particle morphology, and mixer clogging were examined. The advantages of this mixer were identified by comparing with the results obtained using the same chemical conditions with tee-type, cross-type, and central collision-type mixers.