Purpose <p>Pranlukast, a leukotriene receptor antagonist used for the treatment of asthma, has poor water solubility. In this study, pranlukast-containing solid dispersions were prepared using hot-melt extrusion to enhance the oral bioavailability of pranlukast.</p> Methods <p>The optimized pranlukast-containing amorphous solid dispersion, developed using design of experiments (DOEs), was evaluated for its pharmaceutical and biopharmaceutical properties through various analytical methods, including hot-stage microscopy, thermogravimetric analysis, differential scanning calorimetry, solubility measurement in polymer-containing aqueous solutions, Fourier transform infrared spectroscopy, powder X-ray diffraction (PXRD), dissolution testing, and in vivo pharmacokinetic (PK) studies.</p> Results <p>Based on preliminary studies, Soluplus® was selected as the optimal polymer for developing an amorphous solid dispersion with pranlukast. The optimized formulation, containing a 1:4 drug-to-polymer ratio, was processed at a barrel temperature of 210&#xa0;°C and a screw speed of 100&#xa0;rpm. It demonstrated an increased dissolution rate and enhanced oral absorption compared to the commercial product. Stability studies confirmed that the hot-melt extruded pranlukast amorphous solid dispersion remains stable for 24&#xa0;months at 25&#xa0;°C and 60% RH, as determined by PXRD and dissolution studies. Furthermore, the oral bioavailability of the optimized formulation was significantly higher than that of the Onon® capsule, showing approximately 2.5- and 3.3-fold increases in <i>AUC</i>₀ → 12&#xa0;h and <i>C</i>_max, respectively.</p> Conclusion <p>This study confirmed that the hot-melt extruded pranlukast amorphous solid dispersion effectively enhances bioavailability by increasing the dissolution rate and maintains physical stability through optimization using design of experiments (DOEs).</p>