Glibenclamide is a poorly water-soluble BCS Class II antidiabetic drug whose clinical efficacy is limited by low dissolution rate and variable oral bioavailability. This study aimed to formulate and optimize solid dispersions (SDs) of glibenclamide to enhance its aqueous solubility, in-vitro dissolution, and in-vivo bioavailability. Solid dispersions were prepared using solvent-evaporation and hot-melt techniques with hydrophilic carriers (polyvinylpyrrolidone K30, polyethylene glycol 4000/6000, and poloxamer 188) and a hydrophilic surfactant where appropriate. A statistical Design of Experiments (DoE) approach (Box–Behnken design) was used to screen formulation variables (drug:carrier ratio, processing temperature/solvent volume, and surfactant percentage) and to identify optimized conditions. The SDs were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and particle-size analysis to assess physical state, drug–carrier interactions, and morphology. Equilibrium solubility and dissolution profiles (USP paddle method) were compared with pure drug and physical mixtures. Selected optimized SDs were evaluated for pharmacokinetics in a rat model to determine Cmax, Tmax and AUC and estimate relative oral bioavailability. Optimized solid dispersions demonstrated conversion of crystalline glibenclamide toward an amorphous or molecularly dispersed state, suppressed melting endotherm, and absence/reduction of characteristic crystalline peaks. These changes correlated with markedly improved wettability, a faster and higher in-vitro dissolution (complete or substantially increased percent release within the first 30–60 minutes), and significantly greater aqueous solubility compared to raw drug and physical mixtures (p < 0.05). Pharmacokinetic evaluation showed enhanced systemic exposure, indicating improved oral bioavailability of glibenclamide from optimized SDs. The study concludes that appropriately optimized solid dispersion systems can effectively overcome solubility-limited absorption of glibenclamide, offering a promising strategy for improved therapeutic performance.