The name comes from The Royal Belfast Academical Institution which opened its doors in 1814 having been founded in 1810. Originally the square surrounded "Inst" on all four sides, but now only two sides remain: College Square North and College Square East.
One of the most notable buildings in the street is the Old Museum, built as the headquarters of the Belfast Natural History and Philosophical Society in 1831 to a design by Thomas Jackson. The Society rewarded him with honorary membership.