John Neilson of Nethercommon, a Paisley merchant, ordained and appointed in his Will of 1839 that his Trustees "purchase a feu in the town of Paisley ... and erect; a building or buildings thereon, such as they shall consider suitable to the purposes of the Endowment hereby created". That Endowment was the John Neilson Institution; the building, a noteable landmark raising its dome high above the west end of the town, received its first pupils in April, 1852.

From the outset, the policy of the Trustees was most enlightened. While providing generously for Foundationers, children "whose parents have died either without leaving sufficient funds for that purpose, or who from the want of means are unable to give a suitable education to their children", they decided that fee-paying and non-fee-paying pupils should be taught without distinction, and they rejected the view that it was not possible "to blend the rich and the poor together in one large seminary".

The John Neilson Institution always offered a wide range of subjects for study and it is recorded that the senior pupils professed Mathematics, Latin and Greek, Comparative Etymology, Outlines of Astronomy, History, English Language, Prosody, and various subjects coming under the umbrella of Natural Science. Later French and German were added as additional subjects in the curriculum and, possibly as a result of the rich diet provided and the excellence of the pedagogy, by 1870 among former pupils of the Institution could be counted a Professor in Glasgow, a Shaw Fellow, and a Snell Exhibitioner at Oxford.