The selective sono/photocatalytic degradation of methyl orange (MO) in a mixture of methylene blue (MB) by synthesized ZnO/Al2O3 nanocomposites via ultrasound-assisted sol-gel method was studied. The synthesized samples were analyzed by XRD, TEM, EDX, BET, FTIR, UV-vis and Zeta potential analysis. The results showed that the ZnO nanoparticles were hexagonal wurtzite structures that changed to a flake-like quadrilateral morphology by enhancing the Al2O3 dosage. To optimize the selective removal efficiency of MO, response surface methodology (RSM) based on the central composite design (CCD) was applied to study the influence of Al2O3 dosage, catalyst amount, dye concentration and reaction time. A reliability prediction based on a second-order model was achieved with a high coefficient of determination (R2) and adjusted R2 of 0.9914 and 0.9834 for the optimized removal process, respectively. The MO optimal conditions of selective removal efficiency were found at 6.39 wt% of Al2O3 dosage, 32.2mg catalyst amount, 7mg/L of dye concentration and reaction time of 150min to achieve 91.42% removal of MO dye. In the optimal conditions of selective removal, the advanced sono/photocatalytic technique was used to investigate the complete degradation of the adsorbed MO on the catalyst surface. The FTIR spectrum of the MO degradation shows complete removal of some bands compared to the initial control dye, which confirms the degradation of MO after ultrasonic (US) and ultraviolet (UV) irradiation. The use of ZnO/Al2O3 nanocomposites in sonocatalysis process leads to producing electron/hole pairs, whereby the production of reactive oxygen species, MO selected molecules were oxidized quickly.