Computational microscopy is a crucial tool for studying internalization of Au nanohexapods (AuNHs) and can be applied in designing nanostructures for biomedical applications. To further explore the molecular insights into interactions between AuNHs and a plasma membrane (PM), we conducted a coarse-grained molecular dynamic (CGMD) simulation. This simulation aimed to investigate the cellular internalization pathways of AuNHs, considering factors such as sizes (6, 8, 10, and 12 nm diameters) varying rod lengths (LR_S0.6) and spheres at end edges (LR_S0.9), shapes (varying sphere diameters (DS) end edges, and varying pyramid cores (DC) for fixed size at 8 nm AuNH), and surface-charge modifications (neutral and negatively charged). The simulation results indicated that size, shape, and surface modification significantly affect cellular uptake. Each AuNH size facilitated interaction and translocation through the PM by direct permeation and an endocytosis process, utilizing sharp ends or edges to disrupt/penetrate the PM and subsequently enter the inner cell. Direct translocations of shapes (DS and DC AuNHs) were not observed. The surface-charged modification (8 nm sized AuNHs) showed the direct translocation process. When comparing the cellular uptake of shaped AuNHs, the DC AuNH exhibited a higher free-energy barrier. Notably, anionic AuNHs demonstrated the lowest free-energy barrier among the various surface-charged AuNHs compared with neutrally charged AuNHs and bare AuNHs, resulting in anionic charges that were more easily translocated into the inner cell than other shapes and charges. Additionally, the permeability of the surface covering was lower than the unmodified surface due to charges and hydrocarbons facilitating translocation. These findings offer a comprehensive understanding of interactions between AuNHs with various characteristics and a realistic PM, thereby providing insights for the design of nanostructures with biological applications.