This study focuses on evaluations of floating gastroretentive microballoons as a drug delivery system for Repaglinide.It is an oral hypoglycemic agent and the first member of the meglitinide class to be used for the treatment of diabetes mellitus 2. The microballoons were formulated by a solvent evaporation method using ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) as polymers, along with alcohol and dichloromethane as solvents. Microballoon optimization was performed using Design of Experiments (DoE) with a Box-Behnken design.The important parameters, including Percentage Buoyancy (PB) and Entrapment Efficiency (EE), were evaluated to assess the performance of the microballoons.In vitroand in vivoevaluations involved analyzing flow ability parameters, release characteristics of repaglinide using a dissolution apparatus and antidiabetic activity of the microballoons formulation using Streptozotocin-induced diabetic rats as a model. The resulted formulation exhibited high entrapment efficiency (81.12%) and buoyancy (65.02%), suggesting favorable sustained drug release and increased floatability characteristics. Additionally, the formulation showed improved flow ability with a lower Carr's index value of 7.89. It also displayed a lower angle of repose of 25.2 ± 1.7º, indicating enhanced powder cohesiveness and stability. Invitroevaluation of repaglinide microballoons demonstrated sustained release action with B5 optimized batch showing 95.48 % drug in 12 hrs. In vivo studies revealed reduced blood glucose levels up to 10 hours (103.67 mg/dl) for B5 optimized batch, highlighting the potential therapeutic efficacy of the repaglinide microballoons. In conclusion, in vitro and in vivo evaluation of repaglinide floating gastroretention microballoons offers an effective solution for the treatment of diabetes mellitus.