At the clocks strike 11:00 pm -- midnight in Brussels (2300 GMT) -- Britain becomes the first country to leave the 28-member bloc and goes it alone for the first time since 1973.
Prime Minister Boris Johnson has backed Brexit since the 2016 referendum vote to leave that triggered bitterness and division but he has promised to unite the country in a new era of prosperity.
Official celebrations will be muted out of respect for half the population who wanted to stay in the EU and who remain fearful of what lies ahead.
"Our job as the government, my job, is to bring this country together and take us forward," Johnson said in a statement to mark the historic occasion.
He added: "This is not an end but a beginning. This is the moment when the dawn breaks and the curtain goes up on a new act."
Nothing will immediately feel different thanks to an 11-month transition period negotiated as part of an EU-UK exit deal ratified this week.
Britons will be able to work in and trade freely with EU nations until December 31, and vice versa, although the UK will no longer be represented in the bloc's institutions.
But legally, Britain is out -- with no easy way back.
And while the exit terms have been agreed, it must still strike a deal on future relations with the EU, its largest trading partner.
"We will remain friends, allies and partners," Michel Barnier, the EU's chief negotiator in those upcoming talks, told the BBC.
He added his thoughts Friday were with "the millions of British citizens who are sad, as we are sad".
- Divided country -
Getting this far has been a traumatic process.
Despite Britain's resistance to many EU projects over the years -- it refused to join the single currency or the Schengen free travel area -- the 2016 vote to leave was a huge shock.
It unleashed political chaos in London, sparking years of bitter arguments that paralysed parliament and forced the resignations of two prime ministers.
Johnson brought an end to the turmoil with his decisive election victory last month, which gave him the parliamentary majority to ratify the Brexit deal.
But Britons remain as divided as they were nearly four years ago, when 52 percent voted to leave and 48 percent voted to remain in the EU.
Friday's newspapers reflected that continued split, with best-selling eurosceptic tabloid The Sun triumphantly declaring "our time has come" on its front page alongside an image of Big Ben.
But pro-European The Guardian opted for the headline "small island", calling Brexit "the biggest gamble in a generation".
- 'Never coming back' -
Johnson, himself a polarising figure, has emphasised unity and is avoiding any major celebrations that might exacerbate divisions.
He will first host a special cabinet meeting in the northeastern English city of Sunderland, which was the first to declare for Brexit in the 2016 vote.
At 10:00 pm, he will broadcast an address to the nation, and then host a reception for staff at Downing Street.
A light show will also be held outside No 10, while millions of commemorative 50 pence coins are being minted to mark the occasion.
By contrast ex-MEP Nigel Farage, who has spent decades campaigning to leave the EU, is planning a large rally in nearby Parliament Square.
He gave a triumphant speech Wednesday, his last day as a member of the European Parliament, waving Union Jack flags and declaring that Britain was "never coming back".
But afterwards, many MEPs bade Britain an emotional goodbye and broke into a chorus of the traditional Scottish song of farewell, "Auld Lang Syne".
Brussels' Grand-Place was on Thursday lit in red, white and blue.
- Trade talks loom -
British eurosceptics have campaigned for decades to free their country from what they see as an overly bureaucratic and unaccountable institution.
Johnson has promised to leave the EU's single market and customs union so Britain can strike trade deals around the world.
But exactly how that will work -- and at what cost to firms that depend on EU business -- is unclear.
The divorce deal resolved the issue of London's debts, the rights of EU expatriates, the status of Northern Ireland and the transition period.
But Johnson has given himself just 11 months to negotiate a new partnership, covering everything from trade to security cooperation.
He will set out his plans in a speech on Monday but Brussels has already warned he must either limit his ambitions or ask for more time.
Johnson also wants a trade deal with the United States, where President Donald Trump is a big Brexit backer.
Secretary of State Mike Pompeo hailed the potential opportunities during a visit to London on Thursday, saying: "You will see the enormous benefits that accrued to both of our nations as a result of this."