In the present study, zinc oxide (ZnO) nanoparticles were prepared using ZnCl2.2H2O as a precursor, via green route using leaf extract of Rhazya stricta as capping and reducing agent. The prepared ZnO nanoparticles were examined using UV-visible spectrophotometer (UV-Vis), Fourier transform infrared spectrometer (FT-IR), X-ray diffraction spectrometer (XRD), and scanning electron microscope (SEM). The UV-Vis absorption spectrum at 355 nm showed an absorption peak, which indicates the formation of ZnO NPs. The FT-IR spectra analysis was performed to identify the potential biomolecule of the as-prepared ZnO NPs. The FT-IR spectra showed peaks at 3455, 1438, 883, and 671 cm-1 in the region of 4000-500 cm-1, which indicates -OH, NH, C-H, and M-O groups, respectively. The SEM images showed aggregation of ZnO nanoparticles with an average size of 70-90 nm. The XRD study indicated that the ZnO NPs were crystalline in nature with hexagonal wurtzite structure and broad peaks were observed at 2 theta positions 31.8°, 34.44°, 36.29°, 47.57°, 56.61°, 67.96°, and 69.07°. The synthesized ZnO NPs were found to be good antiplasmodial with a 50% inhibitory concentration (IC50) value of 3.41 μg/mL. It is concluded from the current study that the ZnO NPs exhibited noble antiplasmodial activity, and for the improvement of antiplasmodial medications, it might be used after further in vivo studies.