Recent trends indicate that dosage form drug delivery systems are especially suitable for achieving sustained or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducibility. One of the approaches toward this goal was to develop and formulate extended release matrix oral tablets of itopride hydrochloride (ITO) as a highly water soluble drug and to increase its gastric retention time. Matrix tablets of (ITO) were developed using different methods such as: (wetting granulation, direct compression, and coating compression), by using different types of polymers (hydroxypropyl methyl cellulose (HPMC) K15M, hydroxypropyl cellulose (HPC) low viscosity, Eudragit® RL100, and Carnauba wax). The prepared tablets were evaluated according to various physicochemical characteristics such as: weight and thickness variation, drug content, hardness, friability, and in vitro drug release. Tablet weight variation ranged from 395 ± 0.34 to 409 ± 1.78 mg, thickness ranged from 3.16 ± 1.37 to 3.74 mm, drug content ranged from 94.5 ± 1.01% to 106.2 ± 0.08%, friability ranged from 0.04 ± 0.69 to 0.84 ± 0.45, and hardness ranged from 5.25 ± 0.25 to 8.80 ± 0.4 Kg/cm2. Results indicated that drug release depended upon method of preparation and polymer type. Furthermore, in vivo testing of the optimum sustained release tablet formulation (F23) using coating compression by HPMC as coat was performed in human subjects, and determined and compared to that of a commercial oral tablet (Ganaton®) as a reference formulation. The obtained the maximum plasma concentration (Cmax) and the area under the curve from zero to infinity (AUC (0– ∞) values were higher following formulated tablet administration than after Ganaton® administration. The percentage relative bioavailability of ITO from the selected formula in human volunteers was found to be 243% compared to Ganaton®.