The work embodies development and systematic optimization of oral controlled release (CR) mucoadhesive hydrophilic matrices of atenolol using "Design of Experiments". A central composite design was used to optimize drug release profile and bioadhesive strength. Two polymers, namely, Carbopol 934P and sodium CMC, were taken as synergistic factors. The 3-D response surfaces and 2-D contour plots indicated significant effect of both the polymers on ex vivo bioadhesive strength of tablet against porcine gastric mucosa, diffusional release exponent and drug release extension. The optimized drug delivery formulation was selected by feasibility and grid searches based on maximization of the response variables. Validation of drug delivery optimization study using experimental runs indicated high prognostic ability of the chosen experimental design. Besides unraveling the effect of the two factors on various response variables, the study helped in finding the "optimized" formulation with excellent bioadhesive strength and extended release for 24 h, holding immense promise for once-a-day gastroretentive CR formulation and minimizing fluctuations in plasma drug levels.