In the present work, response surface methodology (RSM) was used to determine the mathematical relationship between octenylsuccinic anhydride (OSA) treated maize starch and the octenylsuccinylation reaction conditions. A second‐order polynomial model was chosen to approximate the relationship between the response variable (y, as the degree of substitution “DS” used to define the extent of the octenylsuccinylation) and the three regressors, x₁ as the temperature, x₂ as the time and x₃ as the pH. Analysis of variance (ANOVA) showed a high R² coefficient of 0.9905, thus ensuring a satisfactory adjustment of the selected model with the experimental data. Only temperature‐pH interaction was found to have a non‐significant effect. The positive sign for the regression coefficient of the temperature variable indicated that the y_DS increased with the increased levels of this factor from 25 to 45°C. The negative sign for the coefficient of time and also pH indicated that y_DS decreased as either the time or pH increased in the region of the tested range. The negative coefficients of the interaction between x₂ and x₃ indicated that a simultaneous increase in reaction time with decrease in pH of the esterification reaction led to an increase in y_DS. Maize starch octenylsuccinate synthesis on basis of its DS value was optimized for the three independent variables tested in this study. The predicted value for the DS was 0.02 where temperature, time and pH of the reaction were 28.0°C, 8.1 h, and pH 7.11, respectively. Results of some of the selected physicochemical properties of starch, tested in the present work were also discussed.