Arthur Griffith became central to the Irish Republic when, in October 1921, President de Valera asked him to head the delegation of Irish plenipotentiaries to negotiate with the British government. The delegates set up Headquarters in Hans Place, London. After nearly 2 months of negotiations it was there, in private conversations, that the delegates finally decided to recommend the Treaty to the Dáil Éireann on 5 December 1921; negotiations closed at 2.20am on 6 December 1921.

Griffith was the member of the treaty delegation most supportive of its eventual outcome, a compromise based on dominion status, rather than a republic. After the ratification by 64 votes to 57 of the Anglo-Irish Treaty by the Second Dáil on 7 January 1922, he replaced de Valera, who stepped down in protest as President of the soon-to-be abolished Irish Republic. A vote was held on 9 January to choose between Griffith or De Valera, which De Valera lost by 58 to 60. A second ratification of the Treaty by the House of Commons of Southern Ireland followed shortly afterwards. Griffith was, however, to a great extent merely a figurehead as President of the second Dáil Éireann and his relations with Michael Collins, head of the new Provisional Government became somewhat tense following the Pact negotiations in May.

Under increasing strain because of quarrels with many old friends, and faced with a nation sliding into chaos, Griffith's health deteriorated and he died of a brain haemorrhage on 12 August 1922, at the age of 51, ten days before Michael Collins' assassination in County Cork. He is buried in Glasnevin Cemetery..