Zinc oxide (ZnO) is a well-known semiconductor material due to its excellent electrical, mechanical, and unique optical properties. ZnO nanoparticles are widely used for the industrial-scale manufacture of microelectronic and optoelectronic devices, including metal oxide semiconductor (MOS) gas sensors, light-emitting diodes, transistors, capacitors, and solar cells. This study proposes optimization of synthesis parameters of nanosized ZnO by the electrospinning technique. A Box–Behnken design (BB) has been applied using response surface methodology (RSM) to optimize the selected electrospinning and sintering conditions. The effects of the applied voltage, tip-to-collector distance, and annealing temperature on the size of ZnO particles were successfully investigated. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images confirm the formation of polyvinylpyrrolidone-zinc acetate (PVP-ZnAc) fibers and nanostructured ZnO after annealing. X-ray diffraction (XRD) patterns indicate a pure phase of the hexagonal structure of ZnO with high crystallinity. Minimal-sized ZnO nanoparticles were synthesized at a constant applied potential of 16 kV, with a distance between collector and nozzle of 12 cm, flow rate of 1 mL/h, and calcination temperature of 600 °C. The results suggest that nanosized ZnO with precise control of size and morphology can be fabricated by varying electrospinning conditions, precursor solution concentration, and sintering temperature.