Objective: The objective of the present research work was to formulate and optimize the hydroxyethyl cellulose (HEC) based gastric floating matrix tablets (GFMT) of diltiazem HCl by employing a three factor, three levels statistical design, namely, Box-Behnken design. Materials and Methods: Optimization studies were carried out using Box-Behnken statistical design with three factors, three levels, and 15 runs. Selected independent variables include HEC quantity (X1), %w/w of sodium bicarbonate (X2), and %w/w of Pharmatose (lactose monohydrate) (X3). Cumulative percent drug released at 12 h was selected as dependent variable (Y). Tablets were evaluated for in vitro buoyancy characteristics, in vitro drug release and other tablet characteristics. Results and Discussion: The GFMTâ€™s of diltiazem HCl prepared with HEC fulfilled all the requirements of tablets. Floating lag times for all the prepared formulations were found to be in the range of 156â€“2040 s. The obtained optimum values of the independent test variables are; 93.50 mg quantity of HEC (X1), 11.47% w/w of sodium bicarbonate (X2), and 10.40% w/w of Pharmatose (lactose monohydrate) (X3). The model predicts that the formulation with 100% drug release in 12Â±1 h can be obtained using the above optimum concentrations. Optimized formulation DNAso showed a floating lag time of 405 s. Drug release from DNAs (optimized formulation) and Dilzem SR (commercial sustained release formulation) followed zero-order release kinetics with diffusion mechanism. Conclusion: Results demonstrated that significance of Box-Behnken statistical design in the optimization of critical variables of gastric floating matrix tablets of diltiazem HCl for achieving desired in vitro buoyancy characteristics and in vitro drug release characteristics.