This study reports on the preparation, optimization, and in vitro evaluation of micronized solid dispersions containing Polyethylene Glycol 4000 (PEG4000) and aspirin to increase the dissolution rate of aspirin in water. To achieve this goal, aspirin/PEG4000 composites were prepared and characterized by applying a solid dispersion method with subcritical CO2. Employing response surface methodology (RSM) using the Box-Behnken design (BBD), the effects of different variables including pressure, concentration, drug/polymer ratio, and their interactions on drug content and yield of production were investigated. The closeness between the measured and predicted responses with R2>0.99 demonstrated the validity of the statistical analysis. The optimal formulation obtained from RSM is at a pressure of 63.5 bar, concentration of 0.17 g/gSolution, and drug/polymer ratio of 1. Under the optimized condition, the yield of production and drug content % reached 91.5% and 54.5%, respectively. Dissolution tests carried out in buffer phosphate solution at pH 7.4 showed a significant improvement in dissolution rate, with a rate approximately seven times faster than unprocessed aspirin. In addition, the in vitro drug release profile of produced composites showed an initial burst release of more than 80% in the first 2min.