Glimepiride (GLM), a third‐generation sulfonylurea oral hypoglycemic medication, is used to treat type II diabetes. Admittedly, it has a low bioavailability, a relatively short half‐life (t1/2), and high toxicity. To address the issue, a nanosuspension of poorly soluble GLM is designed using a Quality‐by‐Design (QbD) method, to enhance its solubility. Prospective risk factors are identified and assessed using Critical Material Attribute (CMAs) and Critical Processing Parameter (CPPs) to evaluate the targets by Taguchi orthogonal array (OA) design and to study the effects of formulation and process variables on dependent variables. The amount of Polyvinylpyrrolidone (PVP) (X2), agitation time (X5), and concentration of Poloxamer (X7) are found as significant parameters (p < 0.05), and are further optimized using the Box Behnken Design as response surface methodology model. The optimized GLM nanosuspension 1) has mean particle size (PS), zeta potential, viscosity (VS), and percentage cumulative drug release (CDR%) of 258.17 nm, −25.2 mV, 1.087cPs, and 98.52%, respectively. The pattern of drug release is fitted to Non‐Fickian kinetics. The study results in an economic and efficient nano formulation with enhanced solubility.