Purpose <p>Chitosan, which contains many functional groups, is recognized as an essential component for preparing materials for pharmaceutical use. Chitosan’s cryogels, biocompatibility, biodegradability, and antimicrobial activity make it an attractive candidate for various applications. However, most current studies on chitosan cryogels involve chemical crosslinkers or modifications. Therefore, this work synthesized chitosan cryogel using a green methodology using glycerophosphate electrostatic and thermos-responsive gelation.</p> Methods <p>Sponge-like cryogels were produced and evaluated as a floating drug delivery system with floating properties and morphological examination. In addition to Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), swelling and degradation ratios, drug release studies, and release kinetics were investigated for the ciprofloxacin model drug.</p> Results <p>The study findings revealed that the investigated cryogel has a porous microstructure and a long-lasting floating ability for more than 24&#xa0;h; physicochemical characterizations indicated the successful incorporation of ciprofloxacin into chitosan cryogel, which can sustain drug release for more than 24&#xa0;h.</p> Conclusions <p>Formulated chitosan cryogel can be a promising green approach to improving the effectiveness of oral antibiotic treatment.</p>