Haloperidol is a poorly water-soluble drug, and its efficacy was limited by dissolution behavior. This study aimed to improve haloperidol's dissolution rate by nanonization using rapid expansion of supercritical solution (RESS) process. To design RESS, the solubility data of haloperidol in supercritical CO2 were measured and reported from 3.4 × 10−7 to 1.4 × 10−5 in mole fraction at temperatures from 313.2 K to 333.2 K and pressure up to 22 MPa. The measured solubility data were then correlated using semi-empirical equations with average absolute relative deviations less than 5%. For RESS study, the effects of operating parameters were compared and discussed. The crystal habit of haloperidol was modified from irregular to spherical, and the mean particle size was reduced to 300 nm. Improvement of the dissolution rate was finally verified, and the dissolution rate of haloperidol was enhanced 74 times after the RESS processing.