Silica nanoparticles (SiO2 NPs) are one of the most widely used engineered nanoparticles and can been found in a wide range of consumer products. Despite their massive global production scale, little is known about their potential effects in the context of unintended exposure or ingestion. Using TR146 cells as an in vitro model of the human oral buccal mucosa, the uptake, spatial intracellular distribution, reactive oxygen species (ROS) production, inflammatory response, and cytotoxic effects of commercial SiO2 NPs are examined. SiO2 NPs are shown to dock and cross the cellular membrane barrier in a dose–time-dependent manner. Confocal sectioning reveals translocation of SiO2 NPs into the cell nucleus after 12 h of exposure. A concentration threshold of more than 500 × 10−6 m is observed, above which SiO2 NPs are shown to exert significant oxidative stress with concomitant upregulation of inflammatory genes IL6 and TNFA. Further analysis of the p53 pathway and a series of apoptotic and cell cycle biomarkers reveals intracellular accumulation of SiO2 NPs exert marginal nanotoxicity. Collectively, this study provides important information regarding the uptake, intracellular distribution, and potential adverse cellular effects of SiO2 NPs commonly found in consumer products in the human oral epithelium.