"I am extremely mindful today ... of our European partners for whom this vote will represent a considerable disappointment and a potential setback to many years of effort," Prime Minister Brian Cowen said. "Ireland has no wish to halt the progress of a union which has been the greatest force for peace and prosperity in the history of Europe."
He said the Irish government will "reflect on the implications of this vote," and consult next week at a summit of European Council leaders on how to proceed next.
One option would be to call another vote, considered unlikely given the high turnout and definitive defeat. Another would be to launch a new round of negotiations on the reform, which failed once before with public rejection in France and the Netherlands in 2005.
French President Nicolas Sarkozy and German Chancellor Angela Merkel called for continuing the process of ratification by other member states, which are considering the treaty through their parliaments.
In some cases, heads of state must also sign the document.
Britain is next, with a vote scheduled in the House of Lords next week.
But British opponents of the European treaty were signaling their intent to use the Irish defeat as ammunition to call for a referendum in Britain.
The defeat followed a major push for approval by the Irish government, which contended that the country's economic boom over the past decade has been fueled by access to the European market and the availability of billions of euros in EU subsidies for agriculture and infrastructure.
But a coalition of Irish nationalists, right-wing Catholics, businesspeople and groups leery of the treaty's potential impact on taxes, agriculture and abortion policy argued against the treaty.
Donny Mahoney and Kim Murphy write for the Los Angeles Times