The effects of synthesis conditions (i.e., metal concentration, precursor flowrate, and O 2 dispersion) during flame-spray pyrolysis (FSP) and annealing post-treatment on the characteristics and photocatalytic activities of ZnO nanoparticles have been investigated. The average particle size of ZnO powder prepared by one-step FSP method were in the range of 8.8–47.0nm and were found to be increased with increasing the enthalpy density, flame height, and high-temperature residence time during FSP synthesis. The larger particle size FSP-derived ZnO nanoparticles exhibited higher photocatalytic activities in the degradation of methylene blue (MB) dye. The degradation rate over FSP-ZnO-47.0nm was 1.7 and 7.2 times higher than those of the commercially available photocatalysts Degussa P-25 and JRC-TiO 2 , respectively. The better photocatalytic performance of the FSP-ZnO was correlated well with the improved crystalline quality of ZnO nanoparticles as revealed by the X-ray diffraction (XRD) and the photoluminescence (PL) results. Further increase of FSP-ZnO particle size to 52.6–103.5nm by annealing post-treatment at high temperatures (750–900°C), however, gradually decreased their photocatalytic activities. Our results in this study suggest a balance between high crystalline quality that enhanced photo phenomena and the surface area available for substrate adsorption in order to obtain high photocatalytic activity of ZnO nanoparticles.