The objective of this work was to investigate the effect of ultrasound irradiation on palm oil mill effluent (POME) treatment. The experiment was statistically designed by response surface methodology (RSM) based on central composite design (CCD) to evaluate individual and interactive effects of operational independent variables including ultrasonication amplitude, ultrasonication time and total solids concentration. The treatment performance was assessed by three dependent variables, viz., particle size reduction, total suspended solid reduction and organic solubilisation improvement. Experimental results showed that ultrasonication irradiation has positive effect on POME treatment. The optimum operation condition suggested by RSM were ultrasonication amplitude of 50, ultrasonication duration of 18.94 mins and total solids concentration of 6.47 with expected organic disintegration results as 47.7 particle size reduction, 18.9 of solid reduction and 31.5 of solubilisation improvement. © Published under licence by IOP Publishing Ltd.