Response surface methodology was used to investigate the effect of five selected factors on the selective H2SO4 hydrolysis of waxy maize starch granules. These predictors were temperature, acid concentration, starch concentration, hydrolysis duration, and stirring speed. The goal of this study was to optimize the preparation of aqueous suspensions of starch nanocrystals, i.e., to determine the operative conditions leading to the smallest size of insoluble hydrolyzed residue within the shortest time and with the highest yield. Therefore empirical models were elaborated for the hydrolysis yield and the size of the insoluble residues using a central composite face design involving 31 trials. They allowed us to show that it was possible to obtain starch nanocrystals after only 5 days of H2SO4 hydrolysis with a yield of 15 wt % and having the same shape as those obtained from the classical procedure after 40 days of HCl treatment, with a yield of 0.5 wt %.