Boris Johnson has told his fellow Brexiteers they should not “gloat” about the UK’s departure from the EU, which he said was a cause for “hope not fear”.
The foreign secretary urged people to “unite about what we all believe in”, an “outward-looking, confident” UK.
He also said the result cannot be reversed and that Britain should not be bound by EU rules after Brexit.
And he questioned the economic benefits of being in the EU single market.
Mr Johnson was one of the leading figures in the 2016 Leave campaign.
In his speech in London, he said that holding another referendum on the UK’s membership of the EU would be a “disastrous mistake that would lead to permanent and ineradicable feelings of betrayal”.
He also said the UK must regain control of its regulations and tariffs – and that continuing to be bound by EU directives would be “intolerable” and “undemocratic”.
However, during a transition period immediately after the UK leaves in March 2019 things would “remain as they are”, he said.
Labour MP Chuka Umunna, who supports the Open Britain campaign “against a hard, destructive Brexit”, said Mr Johnson was “totally unqualified to preach about the perils of fear and betrayal”, having “engaged in disgraceful scaremongering” during the EU referendum.
Mr Johnson’s speech is the first in a series of speeches by Theresa May and her ministers on the “road to Brexit”.
The prime minister is expected to address the UK’s future relations with the EU in a speech in Munich on Saturday, the day after she holds talks with German Chancellor Angela Merkel in Berlin.
Mr Johnson made the “liberal case” for the UK’s withdrawal and argued it would allow the country to play a greater role on the world stage.
“We must accept that many [Remainers] are actuated by entirely noble sentiments, a real sense of solidarity with our European neighbours and a desire for the UK to succeed,” he said.
“If we are to carry this project through to national success – as we must – then we must also reach out to those who still have anxieties.
“I want to try to anatomise at least some of those fears and to show to the best of my ability that they are unfounded and that the very opposite is usually true: that Brexit is not grounds for fear but hope.”
He said he accepted he would not “persuade everybody” but added: “In the end these are people’s feelings and people’s feelings matter.”
by Ben Wright, political correspondent, BBC News
It’s a conciliatory tone we haven’t heard much from Cabinet ministers.
And it’s a recognition of the deep divisions Brexit has opened. Boris Johnson will use his Valentine’s Day speech to try to woo despairing Remain supporters who think Brexit is a disaster.
There’s no crumb of comfort for people who would like to see Brexit stopped. Mr Johnson insists it must happen.
Furthermore, he will say the UK must take back full control of regulations and tariff schedules.
It’s no secret the Cabinet is divided on how closely the UK and EU should align after Brexit.
Last month the Chancellor Philip Hammond said he wanted the two economies to move apart only “very modestly”, a statement that enraged Brexiteers.
Boris Johnson’s speech shows again that he is not in the close alignment camp.
His speech was approved by Number 10 and will be scoured for clues about how Theresa May’s divided Cabinet plans to find common ground around the deal it hopes to strike with the EU.
Mr Johnson said the UK would not become more “insular” as a result of Brexit, saying the reverse was true.
“We do not want to haul up the drawbridge and we certainly don’t want to deter the international students who make a huge contribution to our economy.”
Ministers are under pressure to spell out how they can square their desire for frictionless trade after Brexit with the UK’s exit from the single market and customs union, which EU officials say will create trade barriers.
By leaving the customs union, the UK has said it will have freedom to negotiate trade deals of its own during the transition period, while reducing tariffs on imports from developing countries.
Mr Johnson said the benefits of being in the single market and customs union were “nothing like as conspicuous or irrefutable” as claimed by their supporters.
And arguing for independence on setting regulations for businesses, he said British people should not have laws affecting them “imposed from abroad” when they have no power to elect or remove the people making them.
Meanwhile, a report by the Commons Home Affairs Committee has said the UK is ill-equipped to cope with changes to the immigration system after Brexit due to a lack of resources.
The government has yet to set out in detail what type of immigration model it wants to set up outside the EU, when it will no longer be bound by freedom of movement rules from Brussels.
The MPs warned this posed an “immense bureaucratic challenge” and that “rushed and under-resourced changes will put border security at risk”.
Labour MP Yvette Cooper, who chairs the committee, said the government was “kicking the can down the road” with a promised white paper setting out plans yet to be published.
She said this was putting border staff in an “impossible position”.
The Home Office said preparations for Brexit were well advanced and more staff were being recruited.