Synthesis of carboxymethylcellulose (CMC) from natural cellulose is an important industrial process. The effect of process parameters on the synthesis process is important information for the efficiency improvement of production process. Most of the previous studies on the effect of process parameters on the synthesis of CMC are based on the One-Factor-At-Time (OFAT); therefore, in this work, the response surface methodology (RSM) was used. Here, the cellulose was converted to CMC through carboxymethylation process using a technique of William etherification in heterogeneous system. The process parameters studied include the solvent ratio, reaction temperature and reactant ratio (molar ratio of NaOH to SMCA). Meanwhile, the analysis and optimization of the responses of the process, degree of substitution (DS) and yield were also performed using the response surface methodology. The validity of the synthesis process was identified by the determination of CMC spectrum using the fast Fourier infrared spectrometer (FTIR). The analysis of the results shows that carboxymethylation is strongly affected by combination of process parameters studied. The results obtained also show that the optimum responses, degree of substitution (DS) is 0.87 and yield is 1.80, whereas the optimum process parameters, solvent ratio is 0.70v/v, reaction temperature at 56.03oC, and molar ratio of NaOH to SMCA at 1.00mol/mol. These findings conclude that the DS and yield of carboxymethylation of cellulose are strongly affected by the combination of the process parameters.