A church recorded as St. Patrick in insula, meaning St. Patrick on the island, appears in written sources around 1121 and again in the earliest lists of Dublin city parishes from 1179. The island in question was a slight rise of ground between two channels of the River Poddle, and it was onto this pre-Norman foundation that one of medieval Ireland's most consequential building projects was eventually laid.

Archbishop Henry of London began constructing the new cathedral around 1225, and what emerged was the largest church in medieval Ireland: a cruciform structure measuring over 87 metres in length and nearly 49 metres across its transepts, with an aisled nave of eight bays, a Lady chapel added to the eastern end later in the same century, and a tower built against the north side of the western end in 1372. For two centuries, from 1320 to 1520, the building also functioned as Ireland's first university, an arrangement that sits oddly with its later reputation as a purely devotional space. By the sixteenth century it had fallen into considerable disrepair, and much of what a visitor sees today is the product of nineteenth-century reconstruction, which is worth keeping in mind when trying to read the medieval fabric beneath. The south transept is the most rewarding place to look for genuinely early material: it retains original Gothic capitals and sections of vaulting, while the north transept is largely a modern rebuild.

The baptistry holds medieval floor tiles recovered during that same Victorian restoration, reset there rather than discarded. A granite font, formerly fixed to a pier in the western nave aisle, survives with its original dimensions intact. Five pre-Norman graveslabs are preserved inside, along with effigies of identifiable individuals: Fulk de Saundford, who died in 1271, an unnamed thirteenth-century priest or deacon, and an archbishop dating to around 1300 in the south transept. A sequence of wall memorials carries the record further forward, naming figures such as Robert Sutton (d. 1528), Sir Edward Ffitton (d. 1599), and Sir Henry Wallop (d. 1608). The cathedral is open to visitors and sits on Patrick Street in the Liberties; the south porch, a nineteenth-century addition, now serves as the main entrance rather than the original west gable doorway.