The main aim of this work is to develop and thoroughly evaluate resin-based multiparticles of repaglinide for effective management of type-2 diabetes mellitus. Repaglinide was complexed with cholestyramine resin; later the resin complexed drug was encapsulated in ethylcellulose microspheres. The microspheres were characterized for micromeritic properties, SEM analysis, entrapment efficiency, percentage yield, IR spectroscopy, buoyancy behaviour and in vitro drug release in simulated gastric fluid. Microparticles showed regular shape and spherical morphology with entrapment efficiency in the range 51-69%. Differential scanning calorimetry confirmed that there was no chemical interaction between the polymer and the drug. Resin-based microspheres showed good buoyancy behaviour (P < 0.05) due to the presence of bicarbonate ions and sustained release compared to plain drug microspheres (P < 0.05). Finally, the effectiveness of the formulations was evaluated in vivo for blood glucose lowering effect in both normal and streptozotocin-induced diabetic rats. Blood glucose lowering effect induced in diabetic rats by the repaglinide- loaded microspheres was significantly greater (P < 0.05) and prolonged (∼8 h) compared to plain drug microspheres. In a nutshell, floating microspheres containing drug resin complex were able to sustain the drug release in an effective manner for prolonged periods of time and proven in vivo effectiveness by reducing blood glucose level for a longer duration.