The outcome of Britain's referendum instantly pitched an already weakened Europe into a new crisis, opening the possibility that other member states could choose to leave the E.U. and create new headaches for Washington.
American leaders on all sides of the political aisle Friday expressed respect for the decision of British voters and vowed to stand with America's "special relationship" ally Britain and the diminished European Union once both partners have finalized their divorce -- a period that could take years.
But there was no hiding the concern behind the scenes as the shockwaves rippled through the EU, a body that has been vital to American foreign policy initiatives in recent times, including the drive to a nuclear deal with Iran and attempts to punish Russia for its incursion in Ukraine.
President Barack Obama, who felt strongly enough about a British exit or "Brexit" to travel to Britain in April to warn it could not expect special treatment on reaching a free trade deal with the U.S. if it left Europe, offered a rote assurance that nothing would actually change between London and Washington.
"While the UK's relationship with the EU will change, one thing that will not change is the special relationship that exists between our two nations," Obama said during remarks at Stanford University in Palo Alto, California. "That will endure."
But Sir Peter Westmacott, until earlier this year Britain's ambassador in Washington, contradicted the idea that nothing would change in the U.S-British relationship.
"I feel very sad," Westmacott told CNN's Christiane Amanpour, adding that Britain after Brexit would be "less influential in the world, in the European Union, in NATO and the Security Council and a less significant ally for the United States and many others."
"I think we are going to have to paddle even harder with our diplomacy ... to ensure that we continue to ensure that we have our place at the table."
Vice President Joe Biden, the administration's less-filtered voice, was more clear about White House disappointment at the result when he spoke to the issue on a trip to Ireland Friday.
"I must say we had looked for a different outcome," he said in Dublin. "We preferred a different outcome."
For the United States, the possibility that the populist, isolationist victory of the "Leave" vote translates into broader political victories for the movement in Britain and elsewhere in Europe, could mean Washington could eventually find itself straining to get help it has relied on from allies. The UK vote has triggered calls for similar referendums in France, Sweden and the Netherlands, while populist governments already hold power in Greece, Poland and Hungary.
If the Brexit vote results in a domino-like ripple of similar votes or political victories, the experiment of a united Europe could come to an end. It would make the continent less able to help the U.S. push back against Russian assertiveness along Europe's eastern seam, analysts said.
The United States has traditionally relied on an engaged Britain, alongside other allies Germany and France, as a way to ensure its interests are taken into account on the top table of Europe -- and now faces the prospect of one of its most influential allies leaving the block and diminishing its clout.
For the UK, it's not just the EU exit that could cause Britain's influence to wane. If Europhile Scotland now holds a second independence vote, the power of Washington's old ally could be further splintered.
Britain has been a traditional U.S. partner on efforts to stabilize Afghanistan and cooperate in the Middle East on issues ranging from Iran's nuclear program to Israeli-Palestinian peace and the scourge of ISIS. One outcome of the Brexit vote could be "less help from the UK and other NATO allies in the Middle East and elsewhere," said Daniel Serwer, director of the Conflict Management Program at the Johns Hopkins School of Advanced International Studies.
In the short term, a distracted UK, led by a lame duck leader following Cameron's decision to step down, might not have the same capacity or inclination to take on global challenges.
And the economic hit the UK will take as it extricates itself from a market that accounts for 44% of its exports could leave it with fewer resources to do its share. The U.S. is itself already feeling the aftershocks -- American stocks were down more than 600 points at the closing bell Friday afternoon.
Altogether, that could mean a smaller Britain, less able to meet its defense commitments, and it would pose problems for the future of the U.K.'s independent nuclear deterrent, which is based in Scotland and is opposed by the ruling Scottish Nationalist Party.
It could also deepen the U.S. perception that took root under the Obama administration that the U.S. "interests lie more in Asia than in its traditional Atlantic sphere of influence," according to Sebastian Mallaby, a senior fellow at the Council on Foreign Relations, writing in The Washington Post.
Still, American political figures stressed their commitment to the UK despite the change.
House Speaker Paul Ryan, a Wisconsin Republican, tweeted that "the UK is an indispensable ally of the US, and that special relationship is unaffected by this vote."
Sen. Richard Burr, the North Carolina Republican chairman of the Senate intelligence committee, said that "while there will be a great deal of discussion in the coming days and weeks about what the 'Leave' win means for them and for us, our friends and allies in the UK should know this: we respect their decision, and we stand by them, just as they have always stood by us."
The President spoke with British Prime Minister David Cameron and German Chancellor Angela Merkel on Friday to convey the U.S. commitment to both of them, saying afterwards that the EU will remain a "vital" U.S. partner, alongside NATO.
"Our shared values including our commitment to democracy and pluralism ... will continue to unite all of us," Obama said, repeating a common theme in his addresses as criticism of immigrants and religious minorities has featured in the presidential campaign.
But the administration is also looking to adjust to the new reality.
"What was said was we believed in a strong UK voice in a strong EU and that was our position in advance of the referendum," said State Department spokesman John Kirby. "The people of Great Britain have spoken and they want the UK out of the EU that's beyond dispute, and so we now have to move on."
Amid the widespread shock at Britain's decision, Washington is beginning to size up the implications.
"For sure," said Deputy Secretary of State Tony Blinken Friday, "it's going to be a complicated process."