Born in Belfast, Ireland McCullough was a separatist nationalist from an early age. When he was 17, his father had him inducted into the Irish Republican Brotherhood at the side door of a pub by a man who seemed to view the ritual as an unpleasant distraction to a night of drinking. The event disillusioned McCullough with the Brotherhood, and he soon took it upon himself to revitalize the organisation.
He did so over the years with the aid of Bulmer Hobson and Sean MacDermott. Together they founded the Dungannon Clubs for recruitment into the Brotherhood, and they worked to remove the "armchair republicans" from positions of power to be replaced with more determined men. Their cause prospered with the return of veteran Fenian Tom Clarke to Ireland in 1907.
McCullough (Donnchadha Mac Con Uladh) was elected to fill the vacant seat of the President of the IRB late in 1915, a position he held during the Easter Rising of 1916, though he took no active role in the rising itself. He was not a member of the Military Committee that was responsible for its planning (and probably didn't even know of its existence until after the rising). It is likely that the other members of the 3-person IRB executive, Clarke and MacDermott (the treasurer and secretary) supported his nomination as president because, being isolated in Belfast, he would be in no position to interfere with their plans. Nevertheless, during Holy Week he got word of what was afoot and travelled to Dublin to question Clarke and MacDermott, who avoided him as long as they could. Eventually, they informed him of their plans, which he was brought to support.
Though he was an officer of the Irish Volunteers, in charge of 200 men in Belfast, it was decided that Belfast could not take part in the rising, as the dominance of the Ulster Volunteers in the northeast could lead to sectarian civil war. Therefore McCullough was to lead Volunteers in his area to Dungannon, County Tyrone, from where they would link up with Liam Mellows in Connacht. Although the Volunteer's Chief-of-Staff Eoin MacNeill issued a countermanding order, cancelling orders for the rising, McCullough took 150 Volunteers and Cumman na mBan women by train from Belfast to Dungannon. There he found that the local Volunteers under Patrick McCartan did not want to leave their home area and McCullough decided to return to Belfast. During the abortive Rising, he accidentally shot himself in the hand. Nevertheless, he was arrested that week and taken to Richmond Barracks in Dublin. He spent several months incarcerated in Frongoch in Wales and Reading Jail. On his release he married Anne Ryan, daughter of James Ryan.
It has been argued that as President of the Irish Republican Brotherhood at the time of the Easter Rising, the title President of the Irish Republic was by rights his, and not Patrick Pearse's. However, as he had no real role in the planning of the insurrection, and was not in the vicinity of Dublin, where it was clear the leadership would need to be, it is understandable that Pearse was given the title instead.
McCullough's decision not to fight in the Easter Rising lost him his pre-eminent position among Belfast republicans. One, Sean Cusack later said that he told McCullough, "we all felt he had, to some extent, let us down".
McCullough was therefore sidelined in the subsequent Irish War of Independence (1919–1921). He was, however, arrested and imprisoned by the British several times and held for long periods. In 1922, he supported the Anglo-Irish Treaty, despite its acceptance of the Partition of Ireland, as a way of keeping the republican movement united and focussed on the north, where Catholics were being attacked by loyalists. He later said of the split in the southern movement,
"while they were making up their minds about the Treaty, their people inMcCullough was obviously not aware that Collins continued to covertly arm the IRA in Ulster until August 1922, partly to protect nationalists there and partly to try to bring down the Northern Irish state.
the north were being killed day by day. They could not stand up the terror
in Ulster unless they had a united organisation behind them".
After the Treaty, in early 1922 he was sent by George Gavan Duffy (and possibly also by Michael Collins) to the United States to make contact with Irish republican organisations there. He subsequently settled in Dublin in the new Irish Free State.
McCullough's political activity went alongside maintaining and developing an instrument making and retail music business in Belfast’s Howard Street, generated from his original trade as a piano tuner. F.J. Biggar, the solicitor antiquarian and friend of Roger Casement, encouraged its growth with orders for bagpipes for his boy bands. In time, after he moved to Dublin, this became McCullough Pigott of Suffolk Street and marked the beginning of a highly successful and influential Free State business career.
McCullough distinguished himself (inspired by Michael Collins) in forming the New Ireland Assurance Company. A director of Clondalkin Paper Mills, he also had a role in the Irish Army School of Music, and the Gate Theatre. While in America as Special Commissioner for the Free State (leaving his wife in charge of the music business) his new premises in Dawson Street were entirely destroyed by an Anti-Treaty IRA land mine as a reprisal, during the Irish Civil War.
On 20 November 1924, McCullough stood as the Cumann na nGaedheal candidate at a by-election in the Donegal constituency, following the resignation of Cumann na nGaedheal TD Peter Ward. He was elected to the 4th Dáil Éireann, but did not stand again at the next general election, in June 1927.