Sadiq Khan has blasted the Tories for being in denial of the "immense damage" to the country caused by Brexit.
The London Mayor is expected to demand a shift away from the "unnecessarily hard-line version" of Brexit towards greater alignment with Europe.
In a speech in London tonight, he will say: "I simply can't keep quiet about the immense damage Brexit is doing.
"Ministers seem to have developed selective amnesia when it comes to one of the root causes of our problems.
"Brexit can't be airbrushed out of history or the consequences wished away."
His comments may be seen by some as a veiled swipe at Keir Starmer, who has taken a harder stance on Brexit since becoming Labour leader after originally campaigning for Remain.
Mr Starmer has said there's "no case" for rejoining the EU's single market and vowed to fix the gaps in the Government's Brexit deal to then "make Brexit work".
In his first speech of the year, the Labour leader said he would unveil a "Take Back Control" bill as one of his first acts in Government, which would hand greater power to the regions.
The use of the slogan, borrowed from the famous Vote Leave pledge, signals the party's growing confidence in talking about Brexit after years of indecision and infighting.
But the London Mayor, one of Labour's most senior elected politicians, will say that politicians have to accept that "Brexit isn't working".
Mr Khan will point to the economic effects of Brexit, including a reduction of GDP by 5.5%, and set out how to "sensibly and maturely mitigate the damage that's being inflicted".
He will say: "After two years of denial and avoidance, we must now confront the hard truth: Brexit isn't working.
"It's weakened our economy, fractured our union and diminished our reputation. But, crucially, not beyond repair.
"We need greater alignment with our European neighbours - a shift from this extreme, hard Brexit we have now to a workable version that serves our economy and people.
"That includes having a pragmatic debate about the benefits of being a part of the customs union and the single market."
He will acknowledge that "no one wants to see a return to the division and deadlock" of recent years, while arguing that Brexit's detrimental effect "at a time when we can least afford it" must be addressed.
