Engineered nanoparticles (ENPs), such as metallic or metallic oxide nanoparticles (NPs), have gained much attention in recent years. Increasing use of ENPs in various areas may lead to the release of ENPs into the environment and cause the contamination of agricultural and food products by ENPs. In this study, we selected two important ENPs (zinc oxide [ZnO] and silver [Ag] NPs) as potential food contaminants and investigated their toxicity via an in vitro model using Caco-2 cells. The physical properties of ENPs and their effects on Caco-2 cells were characterized by electron microscopy and energy dispersive X-ray spectroscopic (EDS) techniques. Results demonstrate that a significant inhibition of cell viability was observed after a 24-h of exposure of Caco-2 cells to 3-, 6-, and 12-mM ZnO NPs or 0.5-, 1.5-, and 3-mM Ag NPs. The noticeable changes of cells include the alteration in cell shape, abnormal nuclear structure, membrane blebbing, and cytoplasmic deterioration. The toxicity of ZnO NPs, but not that of Ag NPs after exposure to simulated gastric fluid, significantly decreased. Scanning transmission electron microscopy shows that ZnO and Ag NPs penetrated the membrane of Caco-2 cells. EDS results also confirm the presence of NPs in the cytoplasm of the cells. This study demonstrates that ZnO and Ag NPs have cytotoxic effects and can inhibit the growth of Caco-2 cells.