The purpose of the present study was to develop an optimized gastric floating drug delivery system (GFDDS) containing Ondansetron Hydrochloride as a model drug by using various proportions of polymers such as HPMC K4M and Ethyl cellulose. This was employed to enhance the bioavailability and therapeutic efficacy of the drug. The sustained release formulations of Ondansetron Hydrochloride using hydrophobic and hydrophilic polymers were prepared by wet granulation method. Optimization of formulation was done by studying effect of drug to polymer ratio on drug release. FT-IR studies indicated absence of any interaction between Ondansetron Hydrochloride, polymer (HPMC K4M, Ethyl cellulose) and excipients. Six formulations were prepared and formulation F6 possessed good floating property with total floating time between 8-12 hours. The tablets were also evaluated for its hardness, friability, and in-vitro evaluation test. All parameters complied with IP limits. Results of this study indicated that the combinations of hydrophilic polymers with hydrophobic polymers are suitable to optimize sustained release formulation of Ondansetron Hydrochloride.