The objective of present investigation was to develop gastro-retentive controlled release system of carvedilol using biological macromolecule, chitosan. 3² full factorial design was adopted for optimization of tripolyphosphate (X₁) and curing time (X₂). Bead stability in 0.1N HCl, buoyancy duration, density, drug loading, dissolution efficiency and cumulative percentage release at 8th hour were evaluated as dependent variables. The levels of X₁ and X₂ of optimized formulation having maximum desirability was found to 2.0% w/v and 62.66 min, respectively. The in silico predicted responses and observed response were found to be in good agreement (percent bias error: −13.295 to +13.269). SEM images showed numerous pores in the cross sectional image that renders buoyancy. AUC_0-∞ of optimized formulation was 1.47 times higher as compared to suspension corroborating enhanced extent of absorption. T_max and mean residence time were significantly higher from optimized formulation vis a vis suspension. In silico study indicated maximum regional absorption from the duodenum (94.1%) followed by jejunum (5.6%). Wagner-Nelson and Loo-Reigelman method were the preferred deconvolution approach over numerical deconvolution to establish IVIVC. In conclusion, the study showed that gastro-retentive controlled release system prepared using chitosan could be a potential drug carrier of carvedilol with improved bioavailability.