Giant unilamellar vesicles (GUVs) are well-established model systems for studying lipid packing and membrane dynamics. With sizes larger than 1 μm, GUVs are easily observable using optical microscopy. Gold nanoparticles (AuNPs) are well known for their biocompatibility and such biomedical applications in drug and gene delivery as well as medical diagnostics and therapeutics. On the other hand, silver nanoparticles (AgNPs) have long been known for their potent antimicrobial and anti-inflammatory effects for such applications as wound dressing and biomedical implants. In this work, we employed the dark-field microscopy (CytoViva Inc.) to study the interactions between AuNPs/AgNPs and GUVs, respectively. The GUVs used in this study were prepared with 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) as well as cholesterol (chol) at various mol% concentrations (0, 10, 20, 30, 40%). The electroformed GUVs were allowed to incubate with gold or silver nanoparticles of various sizes (between 10 and 100 nm) for 2 hrs before microscopic examination. The experiment has shown that the size of nanoparticles is a critical factor that determines the penetration rate. In addition, the membrane rigidity increases with the molar concentration of cholesterol hence making the NP penetration more difficult. Comparative studies have been made between AuNPs and AgNPs in regard to NP penetration and loading rate as well as the morphological changes induced in GUVs. This work aims to better understand the mechanisms of AuNP/AgNP and membrane interactions for their respective future applications in nanomedicine and nanotechnology.