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Controlled-release microparticles offer a promising avenue for enhancing patient compliance and minimizing dosage frequency. In this study, we aimed to design controlled-release microparticles of Glipizide utilizing Eudragit S100 and Methocel K 100 M polymers as controlling agents. The microparticles were fabricated through a simple solvent evaporation method, employing various drug-to-polymer ratios to formulate different controlled-release batches labeled as F1 to F5. Evaluation of the microparticles encompassed a range of parameters including flow properties, particle size, morphology, percentage yield, entrapment efficiencies, percent drug loading, and dissolution studies. Additionally, various kinetic models were employed to elucidate the drug release mechanism. Furthermore, difference and similarity factors were utilized to compare the dissolution profiles of the tested formulations with a reference formulation. The compressibility index and angle of repose indicated favorable flow properties of the prepared microparticles, with values falling within the range of 8 to 10 and 25 to 29, respectively. The particle size distribution of the microparticles ranged from 95.3 to 126 μm. Encouragingly, the microparticles exhibited high percent yield (ranging from 66 to 77%), entrapment efficiency (80 to 96%), and percent drug loading (46 to 54%). All formulated batches demonstrated controlled drug release profiles extending up to 12 hours, with glipizide release following an anomalous non-Fickian diffusion pattern. However, the drug release profiles of the reference formulation and various polymeric microparticles did not meet the acceptable limits of difference and similarity factors. In-vivo studies revealed sustained hypoglycemic effects over a 12-hour period, indicating the efficacy of the controlled-release microparticles. Overall, our findings suggest the successful utilization of polymeric materials in designing controlled-release microparticles, thereby reducing dosage frequency and potentially improving patient compliance. [ABSTRACT FROM AUTHOR]