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. AUC0-∞ of optimized formulation was 1.47 times higher as compared to suspension corroborating enhanced extent of absorption. Tmax 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.