The present work examines the influence of various process and product parameters on mefloquine hydrochloride (MFL) entrapped in crosslinked chitosan microparticles for masking the bitterness. A central composite design (CCD) was employed to investigate the effect of three process and product variables, namely amount of MFL, chitosan and sodium hydroxide (crosslinking agent) on the incorporation efficiency, particle size, drug release at pH 6.8 and bitterness score. The microparticles were prepared by ionotropic gelation method, with a hardening time of 60 min. The optimum condition for process and product variables was evaluated using desirability function. The model is further cross validated for bias. The optimized microparticles were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the crosslinking of chitosan significantly affects incorporation efficiency, particle size, drug release and bitterness score. The bitterness score was decreased to zero compared to 3+ of pure MFL. It can be inferred that the proposed methodology can be used to prepare MFL microparticles for bitter taste masking.