Response surface methodology is defined as a collection of mathematical and statistical methods that are used to develop, improve, or optimize a product or process. In the present study, a statistical design (Mixture Design) was employed for formulation and optimization of a sustained-release hydrophilic divalproex sodium matrix tablet. Different excipients were used to improve the drug’s poor flowability. The hardness of the prepared tablets and also their release pattern were tested. The formulation design was carried out employing mixture design using four excipients in three levels. The Carr’s index of formulations and tensile strength were determined and analyzed using Minitab software. The suitable formulations regarding flowability and tablet tensile strength were selected by this software for subsequent drug release studies. The dissolution tests were carried out in acidic and basic phases which were previously proved to be biomimetic. Samples were analyzed using HPLC, and release data were compared to Depakine® (sustained-release divalproex from Sanofi). Release kinetics was also determined for selected formulations. Selected formulations were subjected to dissolution test and showed similar dissolution profiles with Depakine® based on difference and similarity factor calculations. The software selected an optimized formulation which had a slightly different release pattern in vitro compared to innovator but of nearly zero-order kinetics. It can be concluded that application of Mixture Design is a shortcut method to design suitable formulations of sustained-release divalproex sodium containing hydrophilic matrix tablets by direct compression method.