The cathedral is built on a traditional east–west axis, with the altar at the eastern end, symbolising belief in the resurrection of Christ.

Negotiations with the colonial government for the grant of five acres of land for a church in the Eastern Hill area began in 1848.

On 1 April 1851, only 16 years after the foundation of Melbourne, the Colonial Secretary of Victoria finally granted the site to the Roman Catholic Church.

Since the Catholic community of Melbourne was at the time almost entirely Irish, the cathedral was dedicated to St Patrick, the patron saint of Ireland.

In 1851 a start was made, but with every able-bodied man in the colony soon rushing to the goldfields, not much was built by 1856, when Goold commissioned a larger one, using a design by Charles Hansom, but only the south aisle was built by 1858 when Goold appointed the recently arrived English architect William Wardell to design a far larger one.

[5] In 1858 William Wardell was commissioned to plan the cathedral with a contract signed on 8 December 1858 and building commencing the same year.

Although the nave was completed within 10 years, construction proceeded slowly, and was further delayed by the severe depression which hit Melbourne in 1891.

Given the size of the Catholic community at the time, the massive bluestone Gothic cathedral was an immense and very expensive undertaking, and there were long delays while funds were raised.

Daniel Mannix, who became Archbishop of Melbourne in 1917, maintained a constant interest in the cathedral, which he was determined to see finished after the long delays during the previous 30 years.

Rather, it underwent significant conservation work, with funds contributed by the federal and Victorian governments, corporate and philanthropic donors and the community of Melbourne.

The cathedral's stained glass windows had buckled and cracked and required a full year to restore to their original state.

Teams of stonemasons and stained-glass craftsmen used "lime mortars and materials long-forgotten by the building trade — like medieval times".

The cathedral's original pipe organ was built in the late 1870s by Robert Mackenzie and completed in 1880 by George Fincham.

The current installation built by George Fincham & Sons, Melbourne in 1962–64 and incorporates a substantial part of the original.

[13] The bells of the cathedral were acquired by Bishop Goold, Melbourne's Roman Catholic leader at the time, when he visited Europe in 1851–1852.

The original manual method was retained by the electronic mechanism, in order to replicate how the bells would have sounded if they were rung by hand.