Synthetic amorphous silica (SAS), manufactured in pyrogenic or precipitated form, is a nanomaterial with a widespread use as food additive (E 551). Oral exposure to SAS results from its use in food and dietary supplements, pharmaceuticals and toothpaste. Recent evidence suggests that oral exposure to SAS may pose health risks and highlights the need to address the toxic potential of SAS as affected by the physicochemical characteristics of the different forms of SAS. For this aim, investigating SAS toxicokinetics is of crucial importance and an analytical strategy for such an undertaking is presented. The minimization of silicon background in tissues, control of contamination (including silicon release from equipment), high-throughput sample treatment, elimination of spectral interferences affecting inductively coupled plasma mass spectrometry (ICP-MS) silicon detection, and development of analytical quality control tools are the cornerstones of this strategy. A validated method combining sample digestion with silicon determination by reaction cell ICP-MS is presented. Silica particles are converted to soluble silicon by microwave dissolution with mixtures of HNO₃, H₂O₂ and hydrofluoric acid (HF), whereas interference-free ICP-MS detection of total silicon is achieved by ion-molecule chemistry with limits of detection (LoDs) in the range 0.2–0.5 µg Si g⁻¹ for most tissues. Deposition of particulate SiO₂ in tissues is assessed by single particle ICP-MS.