Backgroud: Ginsenoside compound K (GK) is a major metabolite of protopanaxadiol-type ginsenosidesand has remarkable anticancer activities in vitro and in vivo. This work used an ionic cross-linkingmethod to entrap GK within O-carboxymethyl chitosan (OCMC) nanoparticles (Nps) to form GKloadedOCMC Nps (GKeOCMC Nps), which enhance the aqueous solubility and stability of GK. Methods: The GKeOCMC Nps were characterized using several physicochemical techniques, including xraydiffraction, transmission electron microscopy, zeta potential analysis, and particle size analysis viadynamic light scattering. GK was released from GKeOCMC Nps and was conducted using the dialysis bagdiffusion method. The effects of GK and GKeOCMC Nps on PC3 cell viability were measured by using the3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Fluorescent technology basedon Cy5.5-labeled probes was used to explore the cellular uptake of GKeOCMC Nps. Results: The GKeOCMC NPs had a suitable particle size and zeta potential; they were spherical with gooddispersion. In vitro drug release from GKeOCMC NPs was pH dependent. Moreover, the in vitro cytotoxicitystudy and cellular uptake assays indicated that the GKeOCMC Nps significantly enhanced thecytotoxicity and cellular uptake of GK toward the PC3 cells. GKeOCMC Nps also significantly promotedthe activities of both caspase-3 and caspase-9. Conclusion: GKeOCMC Nps are potential nanocarriers for delivering hydrophobic drugs, therebyenhancing water solubility and permeability and improving the antiproliferative effects of GK.