Curcumin (CM) possesses multiple biological activities. However, poor water solubility and low bioavailability limit its application in biomedical fields. CM nanoparticles (NPs) (230–240 nm) were prepared by solution-enhanced dispersion via supercritical CO2 (SEDS) (22–22.5 MPa pressure, 31–32.5 °C temperature) and its biological functions were evaluated in this study. The Minimum inhibitory concentration of CM NPs against S. aureus (˜250 μg/mL) was lower than CM-DMSO (˜500 μg/mL). Meanwhile, CM NPs showed effective anti-oxidant ability at a concentration raging from 125 to 2000 μg/mL. CM NPs showed time-dependent intracellular internalization ability, resulting in an enhanced anti-cancer effect on colorectal cancer cells (HCT116), and the mechanism could be explained by cell cycle arrest in G2/M phase associated with inducing apoptotic cells. Moreover, CM NPs exhibited reduced cytotoxicity on normal cells (NCM460) compared to CM-DMSO and 5-Fu. In conclusion, CM NPs prepared via SEDS showed potentials in biomedical applications.