Nanoextrusion was used to produce extrudates of griseofulvin, a poorly water-soluble drug, with the objective of examining the impact of drug particle size and polymeric matrix type–size of the extrudates on drug dissolution enhancement. Hydroxypropyl cellulose (HPC) and Soluplus® were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus®) were fed to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates were dry-milled and sieved into samples with two different sizes. A wet-milled suspension was also spray-dried in comparison to nanoextrusion. Due to differences in polymer–drug miscibility, two forms of the drug were prepared: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nano/microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus® matrix (amorphous solid dispersion, ASD). Under non-supersaturating conditions in the dissolution medium, drug nanocrystals in the HPC-based nanocomposites dissolved faster than the amorphous drug in Soluplus®-based ASD. While smaller extrudate particles led to faster drug release for the ASD, such matrix size effect was weaker for the nanocomposites. These findings suggest that nanocrystal-based formulations could outperform ASDs for fast dissolution of low-dose drugs.