The purpose of this paper was to synthesize ZnO nanoparticles (NPs) from Calotropis gigantea (L.) and use them as photocatalyst for the elimination of wastewater contaminants, methyl orange (MO), and paracetamol (PCM) by UV irradiation. The UV-Vis absorption spectra show a peak at a wavelength of 374 nm with excitonic band gap of 3.41 eV. The hexagonal unit cell with mean crystallite size of 29.13 nm was found from the XRD pattern. The FESEM images confirms the formation of nanostructures. The bio-mediated nanoparticles are used as nano photocatalysts to eliminate MO and PCM. The effects of irradiation time, photocatalyst dose, dye concentration, and solution pH on photodegradation were studied in MO. Furthermore, the photodegradation of paracetamol was also investigated.