Holy Cross College (also known as Clonliffe College), located on Clonliffe Road, Drumcondra, was founded in 1854 as the Catholic diocesan seminary for Dublin by Paul Cullen, Archbishop of Dublin (later created, in 1866, a cardinal).

The College was founded in 1859 by Paul Cullen, Archbishop of Dublin, to provide priests for the Archdiocese of Dublin (Cullen became Cardinal Cullen in 1866). In 1861, the Rector of the Catholic University of Ireland, Bartholomew Woodlock, tried to secure land in Clonliffe west to build a new Catholic University; however, this plan was shelved due to the expansion of the railway line. Plans were drawn up by the architect James Joseph McCarthy for the proposed new University, McCarthy designed the college building.

Following the University Education (Ireland) Act 1879, which incorporated the Royal University of Ireland, the Catholic University of Ireland was reconstituted as to comprise all Catholic Colleges including Holy Cross College, Clonliffe. Students would sit exams for the Royal University. Since the royal university was prohibited in awarding degrees in theology, the Catholic University would confer degrees in theology and divinity, such as BD and DD. Between 1881 and 1908, 81 Clonliffe students graduated with a BA from the Royal University of Ireland.

Following the foundation of the National University of Ireland (NUI) in 1908, Clonliffe's seminarians would have also taken studies in University College Dublin (UCD), and many walked in procession between Clonliffe and Earlsfort Terrace, prior to it moving out to Belfield.

In 1882, the Catholic University of Ireland's Library (excluding medical books) was transferred from what became University College, Dublin, to Clonliffe.

In 1965, Holy Cross College, Clonliffe, the Dublin Archdiocesan Major Seminary, was granted power to confer some of the Degrees of the Angelicum University of Rome, students were awarded degrees such as BD or STB from the Angelicum.

For many years two students from the Vincentian studied at Clonliffe so as to have to opportunity to also gain a degree from UCD, there was a strong relationship between the Diocesan College and the Vincentian order, in that some Vincentian priests from the nearby St. Patrick's Training College and All Hallows would have lectured in Clonliffe. The connection with the Vincentians pre-dated Clonliffe in that students for the Dublin Diocese before the foundation of the College would have initially studied with the Vincentians in Castleknock College before completing their studies in Maynooth College.

In 1977, the National Diploma in Philosophical Studies at 2 year programme validated by the NCEA, and eligible for Higher Education grants was run at Clonliffe, this led in subsequent years to NCEA Certificate and Diplomas in Humanities being offered from Clonliffe.