After working as a typesetter in Dublin and then (1896–98) as a miner and journalist in South Africa, Griffith edited political newspapers such as The United Irishman, Sinn Féin, Eire, and Nationality, and spent his life in near poverty.

Griffith sought to divert the Irish from their attempt to win self-government through legislative action in the British House of Commons. Instead, he urged passive resistance as the way to achieve Irish Home Rule. Irishmen were to refuse to pay British taxes, while Irish members of the Commons were to stay away from Westminster and to sit in Ireland as a national council. At a meeting in Dublin (October 1902), the Cumann nan Gaedheal (Society of Gaels) announced this policy, which was called Sinn Féin. By 1905 the name had been transferred from the policy to its adherents.

Angered by the suggestion that Ireland be partitioned (which he was later constrained to accept), Griffith attacked the unsuccessful third Irish Home Rule Bill (Home Rule) (1912). When the formation of the Ulster Volunteers, who supported the Anglo-Irish union, threatened to lead to violence, he aided the counterorganization of the Irish Volunteers. From the beginning of World War I he opposed Irish participation in the British war effort.

Taking no part in the Easter Rising in Dublin (1916), Griffith lost influence with the extreme nationalists. He recovered his reputation when the British authorities incarcerated him with other Sinn Féin members in Frongoch, a detention camp in Merioneth, Wales (May–December 1916). After their release, Eamon De Valera (de Valera, Eamon) was elected leader. Returning to newspaper work, Griffith was jailed twice more for his anti-British journalism.

After the Sinn Féin electoral victory in December 1918, the Irish members of the House of Commons met as the Dáil Éireann (Assembly of Ireland). They went beyond Griffith's plan, however, and declared for a republic with De Valera as president and Griffith as vice president. During De Valera's long absence in North America (1919–20), Griffith acted as head of the Irish Republic and carried out his own program of civil disobedience.

In the fall of 1921 Griffith unwillingly went to London as the leader of the Irish delegation to the self-government treaty conference. Finally agreeing to exclude six Ulster counties from the republic, he was the first Irish delegate to accept the British terms, later embodied in the Anglo-Irish Treaty (December 6, 1921). Though not satisfied, Griffith insisted that the treaty offered Ireland the best possible opportunity to advance toward full freedom. When the Dáil narrowly approved the treaty (January 8, 1922), De Valera resigned, and Griffith was elected president of the Irish Republic. He was not, however, the head of the new Irish Free State provisional government; Michael Collins (Collins, Michael) had been awarded its chairmanship. Although the two men greatly respected each other, their official actions and utterances were frequently irreconcilable. Opposition to the treaty led to the outbreak of civil war (Ireland) in Ireland (June 28, 1922). Exhausted from overwork, Griffith died soon afterward.