The objective of this study was to prepare the epsilon-viniferine and vincristine-loaded PLGA-b-PEG nanoparticle and to investigate advantages of these formulations on the cytotoxicity of HepG2 cells. Prepared nanoparticle has shown a homogeneous distribution with 113 +/- 0.43nm particle size and 0.323 +/- 0.01 polydispersity index. Zeta potential was determined as -35.03 +/- 1.0mV. The drug-loading percentages were 6.01 +/- 0.23 and 2.01 +/- 0.07 for epsilon-viniferine and vincristine, respectively. The cellular uptake efficiency of coumarin-6-loaded nanoparticles was increased up to 87.8% after 4h. Nanoparticles loaded with high concentrations of both drugs showed a cytotoxic effect on HepG2 cells, having the percentage of cell viability of between 43.23% and 47.37%. Unfortunately, the percentage of apoptotic cells after treated with drugs-loaded nanaoparticles (10.93%) was similar to free forms of drugs (12.1%) that might be due to low epsilon-viniferine release in biological pH at 24h.