Almost half a century as a member of the Brussels club came to an end at 11pm on Friday, with jubilant Brexiteers partying in Parliament Square in Westminster and a light show illuminating 10 Downing Street.
But even Boris Johnson acknowledged there could be "bumps in the road" as the UK moves into a new era, with uncertainty still surrounding the future relationship between Britain and its closest neighbours.
"It is in our common interest to define as close and deep a partnership as possible in defence and security, and in police, judicial, environmental, scientific and cultural co-operation," he wrote in The Times.
"At the same time let me be honest, as I have always been: ease of access to the European market will depend on the degree to which the European Union's rules are accepted, because we cannot allow any harmful competition to develop between us."
With Big Ben silenced as a result of repair work, a projection of Parliament's clock was beamed onto 10 Downing Street and a recording of the famous bongs signalled the moment of the UK's exit from the European Union.
Outside Parliament, Brexit Party leader Nigel Farage hailed "the greatest moment in the modern history of our great nation".
But the Prime Minister struck a more moderate tone, recognising the mixed feelings in a nation that remains deeply divided after years of bitter Brexit battles.
"Tonight we have left the EU - an extraordinary turning point in the life of this country.
"Let us come together now to make the most of all the opportunities Brexit will bring - and let's unleash the potential of the whole UK."
The Prime Minister acknowledged that while for some it was an "astonishing moment of hope" for others there was a "sense of anxiety and loss".
The UK joined the then European Economic Community in 1973 but the 2016 referendum signalled the beginning of the process which resulted in Britain's membership of the bloc coming to an end at 11pm on Friday.
Mr Johnson said his job was now to "bring this country together".
"We want this to be the beginning of a new era of friendly cooperation between the EU and an energetic Britain, a Britain that is simultaneously a great European power and truly global in our range and ambitions," he said.
"And whatever the bumps in the road ahead I know that we will succeed."
There will be few practical changes due to Brexit as the deal negotiated by the UK and EU keeps Britain aligned with EU rules for the rest of the year.
But in a potent symbol of the changed relationship, the Union flag was removed from the European Union institutions in Brussels.
Attention has already turned to the next set of talks aimed at the relationship in trade and other areas which will apply from January 1, 2021.
Brussels is pessimistic about the 11-month timetable for reaching a deal and made clear that Britain will have to accept worse terms and conditions for trade than if it were still a member of the EU.
European Commission president Ursula von der Leyen said: "We want to have the best possible relationship with the United Kingdom, but it will never be as good as membership."
Senior Cabinet minister Michael Gove acknowledged the trade-offs that would have to be made in any deal.
There "will be some regulations that will differ in Britain" so "that may mean that when it comes to trading with Europe there are some bureaucratic processes there that aren't there now", the Chancellor of the Duchy of Lancaster said.
The Daily Telegraph reported that Mr Johnson is prepared to impose full customs and border checks on all European goods entering the UK in an effort to create leverage in the negotiations with Brussels.
The newspaper also said Brussels had issued Britain with a bill for £1.09 billion as it left, as a result of recalculations due to higher gross national income and VAT receipts.
The Prime Minister hosted a reception in Number 10 for senior ministers, officials and supporters of Vote Leave who drank English sparkling wine while the light show was beamed onto the exterior of the building.
Mr Farage told cheering crowds at the rally in Parliament Square: "We did it. We transformed the landscape of our country.
"There are some that say we shouldn't celebrate tonight, but we are going to celebrate tonight."
He added: "The people have beaten the establishment. The real winner tonight is democracy. And I am someone who believes we should be pro-Europe, but not the European Union."
German Chancellor Angela Merkel said Brexit was "a deep break for us all" and warned the "negotiations will certainly not be easy".