Sangelose®(SGL) is a novel hydroxypropyl methylcellulose (HPMC) derivative that has been hydrophobically modified. Due to its high viscosity, SGL has the potential as a gel-forming and release-rate-controlled material for application in swellable and floating gastroretentive drug delivery systems (sfGRDDS). The aim of this study was to develop ciprofloxacin (CIP)-loadedsfGRDDS tablets comprised of SGL and HPMC in order to extend CIP exposure in the body and achieve optimal antibiotic treatment regimes. Results illustrated that SGL-HPMC-basedsfGRDDS could swell to a diameter above 11 mm and showed a short floating lag time (<4 s) and long total floating time (>24 h) to prevent gastric emptying. In dissolution studies, CIP-loaded SGL-HPMCsfGRDDS demonstrated a specific biphasic release effect. Among the formulations, the SGL/type-K HPMC 15,000 cps (HPMC 15K) (50:50) group exhibited typical biphasic release profiles, with F4-CIP and F10-CIP individually releasing 72.36% and 64.14% CIP within 2 h dissolution, and sustaining release to 12 h. In pharmacokinetic studies, the SGL-HPMC-basedsfGRDDS demonstrated higherCmax(1.56–1.73 fold) and shorterTmax(0.67 fold) than HPMC-basedsfGRDDS. Furthermore, SGL 90L in GRDDS indicated an excellent biphasic release effect and a maximum elevation of relative bioavailability (3.87 fold). This study successfully combined SGL and HPMC to manufacturesfGRDDS that retain CIP in the stomach for an optimal duration while improving its pharmacokinetic characteristics. It was concluded that the SGL-HPMC-basedsfGRDDS is a promising biphasic antibiotic delivery system that can both rapidly achieve the therapeutic antibiotic concentration and maintain the plasma antibiotic concentration for an extended period to maximize antibiotic exposure in the body.