Silybin (SLB), a kind of antihepatotoxic polyphenolic substance, is currently available for a variety of acute and chronic liver diseases. However, its poor solubility and low bioavailability have strongly limited its therapeutic applications. In this work, we demonstrate a simple solution to address these issues by designing SLB/poly(vinylpyrrolidone) (PVP) nanodrugs via the aerosol solvent extraction system (ASES). In the ASES process, SLB and PVP are prepared via coprecipitation by using the dimethylformamide/dense gas CO2 solvent/antisolvent strategy. The size of the as-obtained SLB/PVP nanodrugs (denoted as NanoSLB) can be tuned from 100 to 300 nm. Compared with raw SLB, NanoSLB is of low crystallinity and hence shows drug solubility greatly enhanced by more than 8-fold. This work will broaden the applications of water-insoluble drugs in pharmaceutical treatments.