The name of the cemetery comes from an estate established there by the Reverend Stephen Jerome, who in 1639 was vicar of St. Kevin's Parish. At that time, Harold's Cross was part of St. Kevin's Parish. In the latter half of the 17th century, the land passed into the ownership of the Earl of Meath, who in turn leased plots to prominent Dublin families.

A house, Mount Jerome House, was constructed in one of these plots, and leased to John Keogh. In 1834, after an aborted attempt to set up a cemetery in the Phoenix Park, the General Cemetery Company of Dublin bought the Mount Jerome property, "for establishing a general cemetery in the neighbourhood of the city of Dublin".

The first official burial happened on the 19th of September 1836. The buried deceased were the infant twins of Matthew Pollock.

The cemetery initially started with a landmass of 26 acres and grew to a size of 48 acres in 1874.

In 1984, burial numbers were falling, thus the Cemetery was losing revenue and began to deteriorate. A crematorium was needed to regain revenue and deal with plant overgrowth on the estate.

The Funerary Chapel in the cemetery was the first Puginian Gothic church in Dublin. It was designed by William Atkins.

In 2000, Mount Jerome Cemetery established its own crematorium on the site.