Pure and samarium doped ZnO nanoparticles were synthesized by a sonochemical method and characterized by TEM, SEM, EDX, XRD, Pl, and DRS techniques. The average crystallite size of pure and Sm-doped ZnO nanoparticles was about 20 nm. The sonocatalytic activity of pure and Sm-doped ZnO nanoparticles was considered toward degradation of phenazopyridine as a model organic contaminant. The Sm-doped ZnO nanoparticles with Sm concentration of 0.4 mol% indicated a higher sonocatalytic activity (59%) than the pure ZnO (51%) and other Sm-doped ZnO nanoparticles. It was believed that Sm(3+) ion with optimal concentration (0.4 mol%) can act as superficial trapping for electrons in the conduction band of ZnO and delayed the recombination of charge carriers. The influence of the nature and concentration of various oxidants, including periodate, hydrogen peroxide, peroxymonosulfate, and peroxydisulfate on the sonocatalytic activity of Sm-doped ZnO nanoparticles was studied. The influence of the oxidants concentration (0.2-1.4 g L(-1)) on the degradation rate was established by the 3D response surface and the 2D contour plots. The results demonstrated that the utilizing of oxidants in combination with Sm-doped ZnO resulting in rapid removal of contaminant, which can be referable to a dual role of oxidants; (i) scavenging the generated electrons in the conduction band of ZnO and (ii) creating highly reactive radical species under ultrasonic irradiation. It was found that the Sm-doped ZnO and periodate combination is the most efficient catalytic system under ultrasonic irradiation.