For a medieval settlement of any ambition this was unusual, and the reason given is quietly telling: the natural geography may have done the job instead. The name 'Inis' refers to an island, specifically a piece of higher ground formed where a secondary channel of the River Fergus branched off, and it was here, on that modest elevation, that the Franciscan Friary was built around 1270. The surrounding land flooded regularly, the Friary was connected to the O'Brien stronghold at Clonroad by a causeway, and a small castle sat between the Friary's west doorway and the river to protect the quay where goods were unloaded. The town grew between these fixed points, shaped as much by water as by any deliberate plan.

Ennis came into being because the O'Briens, formerly kings of Munster, were pushed westward out of Limerick when the Anglo-Normans arrived. They built earthen ringworks at Clonroad around 1210 and again around 1267, later adding a tower house in about 1470 and a large mansion by 1558. The Franciscans were invited to establish themselves nearby around 1240, and the Friary that followed became the commercial and civic heart of the settlement. In 1543 Murchadh O'Briain accepted English sovereignty and the title of earl of Thomond, and by the end of the sixteenth century the dissolved Friary had been repurposed as a centre of English administration, part of it serving as a prison. In 1600, during the Nine Years War, Hugh O'Donnell of Tyrconnell burned the entire town, sparing only the Friary. Recovery was relatively swift: by 1610 the earl of Thomond had a patent for a Tuesday market and two annual fairs, by 1613 the town had a charter and a self-governing body of twelve burgesses and a provost, and by 1641 a two-storey market-house, arched at ground level for traders and used as a courthouse above, stood where three streets converge at what is now called The Square.

What survives physically is more layered than the Georgian streetscape might suggest. An account written by the attorney Hugh Brigdall in 1682 describes a town of 120 houses, only 12 of them slated and the rest thatched, with a population of between 500 and 600 people. A number of seventeenth-century buildings remain identifiable: McParland's house has a gable dated to around 1600 and internal timbers from 1672; Cruise's retains an intact west gable with a datestone of 1658; houses on all three main streets preserve Jacobean-style chimneys. Henry Ellsworth's survey map of 1634 and Thomas Moland's pictorial map of 1703 both show a street layout that is recognisably the one in use today, which means that walking the older lanes of Ennis is, in a fairly literal sense, tracing a plan that has not substantially changed in nearly four centuries.