Sulpiride (SUL) is a dopamine D2-receptor antagonist used for management of GIT disturbance and it has anti-psychotic activities based on the administered dose. SUL undergoes P-glycoprotein eux, which lead to poor bioavailability and erratic absorption. Therefore, the objective of this research was an attempt to enhance the oral bioavailability of SUL via formulation of fast disintegrating tablets (SUL-FDTs) with a rapid onset of action. A32 full-factorial design was performed for optimization of SUL-FDTs using desirability function. The concentration of superdisintegrant (X1) and Prosolv® (X2) were selected as independent formulation variables for the preparation and optimization of SUL-FDTs using direct compression technique. The prepared SUL-FDTs were investigated regarding their mechanical strength, disintegration time, drug release and in vivo pharmacokinetic analysis in rabbits. The optimized formulation has hardness of 4.58  0.52 KP, friability of 0.73  0.158%, disintegration time of 37.5  1.87 s and drug release of 100.51  1.34% after 30 min. In addition, the optimized SUL-FDTs showed a significant (p 0.01) increase in Cmax and AUC(0–1) and a relative bioavailability of about 9.3 fold compared to the commercial product. It could be concluded that SUL-FDTs are a promising formulation for enhancing the oral bioavailability of SUL concomitant with a fast action.