The aim of the present investigation was to prepare and optimize the formulation of mouth dissolving film of salbutamol sulphate by applying experimental design technique. The films were prepared using hydroxypropyl methylcellulose, polyvinyl pyrrolidone and polyvinyl alcohol by solvent evaporation technique. Simplex lattice design and desirability function were adopted for the preparation of film possessing desirable and optimized characteristics. Tensile strength, elastic modulus, percentage strain, load at yield, and percentage drug release were selected as dependent variables. Regression equations and contour plots were used to relate the dependent and independent variables. The concept of similarity factor S(d) was used to prove similarity of dissolution between distilled water and simulated saliva (pH = 6.8). The polymers greatly influenced the mechanical properties and % drug release from the film. From the computed value of desirability function, it was determined that the film containing hydroxypropyl methylcellulose and polyvinyl alcohol was the best batch. The experimental design serves to be a useful tool for the formulation development of mouth dissolving film.