This paper presents the strategy for nanoparticle design of theophylline using rapid expansion of supercritical solutions (RESS) technique. In this study, the production of nanoparticles of theophylline via the RESS technique using supercritical CO2 has been presented. The effects of five different operating parameters including equilibrium temperatures (313.2, 323.2, and 338.2 K), equilibrium pressures (14.0–22.0 MPa), pre-expansion temperatures (333.2–373.2 K), nozzle temperatures (323.2–383.2 K), and collection temperatures (265–303 K) on the size and morphology of the nanoparticles were investigated. The mean size of the produced particle was in the range of 200–300 nm, which was about 1/300 of the size of the unprocessed particle. Furthermore, the results of summarizing the dependence of the five operating parameters on particle size showed that nanoparticle size was strongly influenced by supersaturation between the pre-expansion and post-expansion sections. The supersaturation-based design will enable the control of nanoparticle size produced using the RESS technique.