O'Malley was educated at the Jesuit Crescent College and at University College Dublin, from which he graduated with a degree in law in 1962. In 1968, after Donogh O'Malley died suddenly, Desmond O'Malley was elected to Dáil Éireann for Fianna Fáil in the subsequent by-election in the Limerick East constituency. At the time it was believed that this by-election victory was partly due to Neil Blaney and his "Donegal Mafia".
Following the 1969 general election O'Malley was appointed Parliamentary Secretary to the Taoiseach, Jack Lynch, and also Parliamentary Secretary to the Minister for Defence, Jim Gibbons. O'Malley had a central role in the prosecutions that arose from the Arms Crisis of 1970. The case against the accused government ministers Charles Haughey and Neil Blaney was dismissed in the Supreme Court, and both ministers were acquitted.
In 1970 O'Malley succeeded Micheál Ó Móráin as Minister for Justice. His plans to introduce internment without trial for Provisional IRA suspects in the Republic were not implemented, but he was the subject of an assassination threat, was forced to carry a loaded pistol and was frequently moved from house to house.
On 1 October 1982, another challenge to Haughey was initiated by the Kildare TD, Charlie McCreevy. O'Malley was on holiday in Spain at the time but rushed back to put his own name forward as a possible alternative to Haughey. He and his supporters resigned from the Cabinet. Haughey won an open vote by 58 votes to 22, with the result that those TDs who voted against Haughey, including O'Malley, became known as the Gang of 22.
In 1983 a Fine Gael–Labour Party coalition government took office and its Minister for Justice, Michael Noonan, revealed that Haughey's government had been involved in the tapping of certain journalists' telephones. This set off another leadership struggle, with O'Malley, Gerard Collins, Michael O'Kennedy, Brian Lenihan and John P. Wilson all showing an interest in replacing Haughey. However, an official inquiry into the telephone tapping cleared Haughey of any wrongdoing and put more blame on Martin O'Donoghue than the other TDs involved. Haughey reatined the leadership by 40 votes to 33.
George Colley died in 1983 and Martin O'Donoghue was no longer a TD. O'Malley became isolated within Fianna Fáil, with many of his supporters giving up hope of ever beating Haughey.
In early 1985 a bill was introduced by the Fine Gael–Labour Party government to liberalise the sale of contraceptives. Fianna Fáil opposed the bill, but O'Malley considered it a matter of conscience and wanted to support it. When it came to a vote he abstained. On 26 February 1985 he was summoned to a party meeting and charged with "conduct unbecoming". Following a roll-call vote he was expelled from Fianna Fáil by 73 votes to 9.
In 1990 Fianna Fáil's nominee in the presidential election was Brian Lenihan. A few weeks before the election a scandal broke over the accusation that Lenihan had phoned President Hillery in 1982, asking him not to dissolve the Dáil following the fall of Garret FitzGerald's government. Lenihan had always denied this, but now new evidence had come to light. O'Malley told Haughey that the Progressive Democrats would pull out of the coalition and support a no-confidence motion tabled by the opposition unless Lenihan left the government or Haughey opened an investigation into the incident. Haughey sacked Lenihan.
In early 1992 the programme for government was up for renewal. When it was revealed by Seán Doherty that Haughey had authorised the tapping of two journalists' telephones in 1982, O'Malley decided that the Progressive Democrats could no longer remain in his government. Haughey resigned on 11 February 1992 and was replaced as party leader and Taoiseach by Albert Reynolds. O'Malley and the Progressive Democrats continued in the coalition until Reynolds accused O'Malley of being "dishonest" while giving evidence to the Beef Tribunal. The collapse of the coalition led to the general election. Fianna Fáil returned to power in coalition with the Labour Party and the Progressive Democrats moved into Opposition.
{{Navboxes |title=Desmond O'Malley |list1=