In the present work, the degradation of Direct Red 81 by ozonation was studied. The interactive effects of the influencing factors (dye concentration = 500-2,000 mg/L; time = 10-30 min; pH = 7.0-11.0) on degradation efficiency was critically examined through experimental design optimization by central composite design under the response surface methodology. The high correlation coefficients (R2 = 0.976 & adjusted R2 = 0.958) obtained by analysis of variance (ANOVA) demonstrated close fit between the experimental and the predicted values. Optimized conditions under specified cost-driven restraints were obtained for the highest desirability (i.e. degradation of 1,210.59 mg/L dye) at pH = 11.0, initial dye concentration = 2,000 mg/L and ozone exposure time of 27.16 min. The degradation of Direct Red 81 was confirmed through Fourier transform infrared spectroscopy (FTIR) analysis and UV-Vis spectrometry.