A series of tris(hydroxymethyl)aminomethane (TRIS)-based linear (bis(TRIS)) and triangular (tris(TRIS)) ligands has been synthesised and were covalently attached to the Wells–Dawson type cluster [P2V3W15O62]9− to generate a series of nanometer-sized inorganic–organic hybrid polyoxometalate clusters. These huge hybrids, with a molecular mass similar to that of small proteins in the range of ≈10–16 kDa, were unambiguously characterised by using high-resolution ESI-MS. The ESI-MS spectra of these compounds revealed, in negative ion mode, a characteristic pattern showing distinct groups of peaks corresponding to different anionic charge states ranging from 3− to 8− for the hybrids. Each peak in these individual groups could be unambiguously assigned to the corresponding hybrid cluster anion with varying combinations of tetrabutylammonium (TBA) and other cations. This study therefore highlights the prowess of the high-resolution ESI-MS for the unambiguous characterisation of large, nanoscale, inorganic–organic hybrid clusters that have huge mass, of the order of 10–16 kDa. Also, the designed synthesis of these compounds points to the fact that we were able to achieve a great deal of structural pre-design in the synthesis of these inorganic–organic hybrid polyoxometalates (POMs) by means of a ligand design route, which is often not possible in traditional “one-pot” POM synthesis.