The purpose of this investigation was to design and develop gastroretentive dosage form for levofloxacin hemihydrate using floating tablet approach with various grades of hydroxypropyl methyl cellulose. Levofloxacin highly soluble in acidic media and precipitates in alkaline media thereby losing its solubility. Hence, a gastro retentive system was developed to enhance the bioavailability and therapeutic efficacy by retaining them in the acidic environment of the stomach. Sodium bicarbonate was used in the dosage form as a source of carbon-di-oxide to maintain buoyancy. In vitro dissolution study results indicated non-Fickian diffusion controlled drug release mechanism and was best fitted into zero-order equation. In vivo radiographic studies conducted in healthy human volunteers for optimized formulation indicated over 5 h retention of tablet in the stomach region. Reproducible physical parameters indicated that the current formulation could be easily scaled-up.