Senator George Mitchell has said a Brexit outcome that avoids a hard border between Northern Ireland and Ireland must be encouraged.
And he urged those grappling with the issue to seek inspiration from the Good Friday Agreement, which brought peace 20 years ago.
"We must encourage a Brexit outcome that does not re-establish a hard border between Northern Ireland and Ireland," Mr Mitchell said.
"The governments of the US and the UK must avoid any economic decisions that cost jobs or create hardship in Northern Ireland."
The senator made the comments at an event at the Library of Congress in Washington DC on Tuesday night to mark the 20th anniversary of the Good Friday Agreement.
Mr Mitchell was instrumental in brokering the accord.
"When I announced the Good Friday Agreement 20 years ago I described it as an historic achievement and it was," Mr Mitchell said.
"But I also said on that day, that by itself the agreement did not guarantee peace, or political stability or genuine reconciliation in Northern Ireland.
"It made them possible but achieving and sustaining those lofty goals would require of future leaders the vision and the courage that the leaders of Northern Ireland demonstrated in 1988."
Life is change, that is true of societies as it is of individuals, he said.
He added: "As they today reflect on their responsibilities I hope that the current leaders of Northern Ireland, of Ireland, of the United Kingdom and of the European Union look back 20 years to what their predecessors were able to do."
The senator said President Clinton was the first American president to make peace in Northern Ireland a central objective of his administration.
"He jumped in where others feared to tread and he deserves great credit," Mr Mitchell said.
But he added that the real heroes of the accord were the people of Northern Ireland and their political leaders.
"In dangerous and difficult circumstances after lifetimes devoted to conflict they summoned extraordinary courage and vision and reached agreement at great risk and cost to themselves their families their political careers.
"We should not hold Northern Ireland to a higher standard than we apply to ourselves and to others.
"And surely as we assemble here in the Library of the United States Congress no American should be preaching to others about political dysfunction and the same caution apples to the UK at this time."
After devoting so many years to the peace process Mr Mitchell said those years changed his life.
"I've come to know and love Ireland and its people," he said.
He added: "A lot of people thank me for my work in Northern Ireland.
"My response to them is that it is I who should be grateful - and I am because the Irish have filled an inner void that I didn't know existed.
"I am an American, very proud of it, but a large part of my heart and of my emotions will forever be with the people of Ireland and Northern Ireland."