Recent work aimed to prepare nanosuspension of glimepiride by using antisolvent evaporation followed by sonication technique. As glimepiride belongs to BCS class II, thus it has less solubility and high permeability. Hence to enhance the solubility of glimepiride, it was formulated into nanosuspension. Different polymers were used to prepare stable nanosuspension by taking several trial batches. After getting the results from trial batches, the combination of Pluronic F68 and PEG 400 was selected for the preparation of glimepiride nanosuspension by using a 32 full factorial design. After evaluation of nine formulation batches, batch FG8 showed the highest %Entrapment efficiency of 85.3 ± 0.73 %. In comparison to other batches, the FG8 batch showed a percent total drug content of 96.40 ± 0.4 % which was the highest one. All batches of nanosuspension were evaluated for different parameters; in that batch, FG8 showed the minimum particle size of 177.1 ± 0.08 nm, low polydispersity index of 0.142 ± 0.01, and highest zeta potential of 33.0 mV respectively. In comparison to the release of pure drug glimepiride, an in-vitro dissolution study showed that batch FG8 had a maximum release of 97.6% at 60 minutes. The optimization was carried out mostly using a linear model. Following the study and collecting the ANOVA results, it was revealed that the FG8 batch was an optimized batch by using the combination of Pluronic F68 and PEG 400 a stable nanosuspension was formulated which enhanced the solubility followed by dissolution of pure glimepiride drug.