The study aimed to formulate and evaluate sustained release ondansetron tablet. Conventional ondansetron tablets not only produce rapid and relatively high peak blood levels resulting in adverse effects but also should be administered three to four times daily. These drawn backs can be overcome by designing a suitable sustained release formulation. Sustained release tablets of ondansetron to be taken once daily were formulated with ondansetron hydrochloride equivalent to 8 mg of ondansetron base. Matrix system based on swellable as well as non-swellable polymers was selected for sustaining the drug release. Different polymers such as hydroxypropylmethylcellulose (HPMC), Carbopol were studied. Combinations of non-swellable polymers with HPMC were also tried in order to get the desired sustained release profile over a period of 24 h. The effect of drug to polymer ratio on in vitro release was studied. The marketed formulation was evaluated for different parameters such as appearance, weight variation, drug content and in vitro drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in six healthy human volunteers and the pharmacokinetic parameters.