This study focuses on the formulation and evaluation of floating microspheres containing Cefuroxime axetil, a broad-spectrum cephalosporin antibiotic, to create a gastroretentive drug delivery system. The goal is to enhance the drug's oral bioavailability by prolonging its residence time in the stomach. Preformulation studies established Cefuroxime axetil's properties: a light-yellow crystalline powder with a bitter taste, soluble in water and 0.1 N HCl, and freely soluble in ethanol, methanol, and chloroform. Its melting point was 132−135∘C, and its λmax was 282.0 nm. The floating microspheres were prepared by the solvent diffusion-evaporation method using HPMC and EC polymers. Formulation F3 was identified as the optimum batch, demonstrating the highest percentage yield (73.32±0.65%), maximum drug entrapment efficiency (75.56±0.23% w/w), and highest buoyancy (76.65±0.52%) with a short floating lag time (32±4 sec). In vitro release studies for the optimized F3 formulation showed sustained drug release, following Zero-order kinetics (R2=0.958). The conclusion is that this delivery system successfully achieves a prolonged gastric residence time and continuous drug release, thereby improving Cefuroxime axetil's absorption and efficacy.