Purpose: To prepare orally disintegrating tablets (ODT) of montelukast sodium using Design-Expert for improved patient compliance. Methods: Central composite design was selected to delineate and optimize the formulations. Concentrations of crospovidone (X1) and sodium bicarbonate (X2) were selected as the variables, and responses were based on friability (Y1) and disintegration time (Y2). Varying amounts of super disintegrating agents and effervescent bases were used with microcrystalline cellulose to prepare montelukast sodium ODT. Results: Carr's index of montelukast sodium was 4.76±0.075, indicating the good compressibility of powder. Whereas the Carr's value for microcrystalline cellulose and mannitol were 30.14±0.021 and 22.41±0.053 respectively. The FTIR spectra indicated that there were no major shifting and loss of functional groups in drug and excipients blends. Formulations were evaluated, check point batch (CPB, F2) was selected using Design-Expert. The friability of CPB tablets was found to be 0.27 ± 0.085;