Archaeological work in the town suggests that the street follows the original high-tide mark of a Viking settlement built around a deep-water inlet called the Pool, the curved space now occupied by the Crescent. Most of the ground to the east of Main Street turns out to be composed of silts and infill, material deposited or reclaimed over centuries, while the oldest occupation layers are expected to lie to the west, close to where that pool once opened. The Viking town itself covered roughly six hectares, and excavations at the junction of Bride Street and Main Street have confirmed Viking-period settlement material at that spot. The defences of the Norse town have not yet been located by excavation, but they were probably an earthen rampart fronted by a fosse, a defensive ditch, running from the seashore near the later castle site, crossing Bride Street and Peter Street, and returning to the harbour somewhere around Cornmarket.

The Anglo-Normans who took the town in 1169 burned its extra-mural suburbs in the process, and in the following centuries they built their own stone walls along much of the same line as the earlier Norse earthworks, eventually enclosing an area of around eighteen hectares. No murage grants, the royal licences that typically funded medieval wall-building, survive for Wexford, but tradition holds that the walls were begun under King John and completed around 1300. The town received its first formal charter from Aymer de Valence in 1318, and further charters followed in 1410, 1538, and 1609. By 1307 the town contained 365 burgages, the standard unit of urban property in a medieval town, a figure that had barely shifted to 345 by 1537, suggesting a settlement that had reached a kind of plateau rather than grown. From the fourteenth century, silting of the harbour restricted the size of vessels that could enter, setting the town into gradual decline and leaving it increasingly outcompeted by the deeper ports of New Ross and Waterford. By 1682, the town was described as half-depopulated, the herring fishery having collapsed. During the Confederate Catholic occupation at the end of 1641, a fosse eight feet deep and twenty-four feet wide was dug outside the walls, and a rampart was added inside before Cromwell took the town in October 1649, traces of which are still visible in places.

Considerable stretches of the medieval town wall survive and can be traced across several parts of the modern street plan: a section at the south-west corner off Bride Street, a run from St Patrick's church to Mary Street, a portion with a rectangular tower west of Mallon Street, and a section with a circular tower near the Cornmarket continuing as far as George's Street. Of the six known medieval gates, only one, now called the Westgate, still stands. Its survival is slightly accidental: it was associated with St Selskar's church rather than a public thoroughfare, so when the Corporation began clearing the town's gates as obstructions in the eighteenth century, this one was left alone.