Manufactured nanomaterials (MNMs) often have a surface-chemical modification in order to tailor their physicochemical properties, including also powder properties and miscibility. Surface-chemical modifications may influence the toxicological properties of the MNM, but the specific chemistry and extent are rarely described in detail in suppliers’ technical data sheets. Chemical and quantitative information on any surface-chemical treatment, coating and functionalization are required for chemicals registration in Europe. Currently there is no globally accepted and documented approach to generate such data. Consequently, there is a continued research need to establish a structured approach to identify and quantify surface-chemical modifications. Here we present a tiered approach starting with screening for mass-loss during heating in a furnace or thermogravimetric analysis (TGA) followed by solvent extraction, and analysis by several mass spectrometry (MS) techniques depending on the target analytes. Thermal treatment was assumed to be able to quantify the amount of organic coating and MS was used to identify the extractable organic coatings after pressurized liquid extraction (PLE) using methanol at 200 °C. Volatile organic compounds in extracts were identified with gas chromatography and MS (GC-MS), non-volatile organic compounds with liquid chromatography MS (LC-MS), and polymeric compounds with matrix-assisted laser desorption ionization time-of-flight MS (MALDI-TOF-MS). The approach was demonstrated by analysis of 24 MNM, comprising titanium dioxide, synthetic amorphous silica, graphite, zinc oxide, silver, calcium carbonate, iron oxide, nickel-zinc-iron oxide, and organoclay. In extracts of 14 MNMs a range of organic compounds were identified and the main groups were silanes/siloxanes, fatty acids, fatty acid esters, quaternary ammonium compounds and polymeric compounds. In the remaining 10 MNMs no organic compounds were detected by MS, despite the fact an organic coating was indicated by TGA.