Cybi was born somewhere in Cornwall in the late 5th century, travelled widely through Wales, Ireland, and Brittany, and arrived on Holy Island in middle age looking for a final base. The monastery he founded inside the Roman walls in 540 was small - a wooden church, some cells for the brothers, a well. He died on 8 November 555 and was buried in the churchyard. A tiny separate chapel called Eglwys y Bedd (the Church of the Grave) still stands a few metres from the main church on what is thought to be his original tomb. The island took his name - Caer Gybi means Cybi's Fort - and in Welsh the whole town of Holyhead is still called Caergybi. He is remembered in Wales as one of the seven blessed cousins of Saint David, the patron saint of the country.

In the 10th century, Viking raiders working the Irish Sea coast sacked the original church and the monastic buildings. The community rebuilt. In 1405, the church was burned again, this time by Henry IV's English army, who had crossed from Ireland to put down the Welsh rebellion of Owain Glyndwr; the soldiers carried off Cybi's shrine and his relics, which were never recovered. The present church was built in stages between the 13th and 16th centuries, with the chancel - the eastern, altar end - dating to the 13th century and counting as one of the oldest parts of the building. Then came the worst visit of all. In the 1650s, during the English Civil War, Oliver Cromwell's Parliamentary army quartered itself in the church. The soldiers smashed statues, defaced the font, broke the memorials, and shattered the stained glass. They also added 17 feet to the height of the tower so they could use it as a lookout over the harbour. The improvised garrison block is still there above the original tower, the join clearly visible in the stonework.

In 1897 the church gained an extension that would not have looked out of place in a Westminster cathedral. The Stanley Chapel, designed by the Victorian architect Sir Gilbert Scott, was added to the south side for the prominent local Liberal politician William Owen Stanley. Inside it stands a life-size figure of Stanley carved from Carrara marble by Hamo Thornycroft - the same sculptor who did the bronze of Oliver Cromwell that stands outside Parliament. The juxtaposition is quietly ironic: Cromwell's army wrecked the church; two centuries later, Cromwell's sculptor adorned it. On the south transept wall a sundial bears the Welsh inscription Yr hoedl ar hyd ei haros a dderfydd yn nydd ac yn nos - life, though long it stays, will end in night and day. In 2024, archaeologists excavating in the churchyard for restoration work turned up Roman pottery and medieval burials, and confirmed that the long thread of continuous Christian use - from Cybi to today - is one of the longest documented anywhere in Wales.