The present work investigates the formulation and biopharmaceutical estimation of gastric floating drug delivery system (GFDDS) of propranolol HCl using semi-synthetic polymer carboxymethyl ethyl cellulose (CMEC) and a synthetic polymer polyethylene oxide (PEO). A central composite design was applied for optimization of polymer quantity (CMEC or PEO) and sodium bicarbonate concentration as independent variables. The dependent variables evaluated were: % of drug release at 1 hr (D1hr), % drug release at 3 hr (D3hr) and time taken for 95% of drug release (t95). Numerical optimization and graphical optimization were conducted to optimize the response variables. All observed responses of statistically optimized formulations were in high treaty with predicted values. Accelerated stability studies were conducted on the optimized formulations at 40 ± 2°C/75% ± 5% RH and confirm that formulations were stable. Optimized formulations were evaluated for in vivo buoyancy characterization in human volunteers and were found buoyant in gastric fluid. Gastric residence time was enhanced in the fed but not the fasted state. The optimized formulations and marketed formulation were administered to healthy human volunteers and evaluated for pharmacokinetic parameters. Mean residence time (MRT) was prolonged and AUC levels were increased for both optimized floating tablets when compared with marketed product. High relative bioavailability obtained with optimized gastric floating tablets compared to commercial formulation, indicated the improvement of bioavailability.