Wes Streeting has said Labour must change course if it is to stand up to Reform UK, warning the Labour government is losing the fight against "nationalism".
In his resignation speech to MPs, he said it represented an "existential threat" to the future of the UK.
The former cabinet minister delivered the speech in the Commons, after quitting as health secretary on Thursday, saying he had lost confidence in Sir Keir Starmer's leadership.
The prime minister is resisting calls to set a timetable for his departure following ministerial resignations, and Labour's election losses in England, Scotland and Wales earlier this month.
Streeting said: "I left the government because we are in the fight of our lives against nationalism, and it is a fight that we are currently losing.
"Unless we change course, we risk handing the keys of No 10 to Reform, and I do not want that on our consciences.
"For the first time in our history, nationalists are in power in every corner of the United Kingdom.
"Scottish and Welsh nationalism represents an existential threat to the future integrity of the United Kingdom.
"And Reform UK represent a threat to the values and ideals that have made this country great."
He told MPs he believed Labour could still deliver "real change",
In his speech, the Ilford North MP listed his achievements as health secretary before summing up his vision using the quote from cancer awareness campaigner Deborah Jones, known as Bowel Babe, that he was full of "rebellious hope".
Streeting was surrounded by supporters on the green benches as he gave the 20 minute speech, flanked by Jess Phillips, who quit as safeguarding minister last week, and Rosie Wrighting, who also resigned her role as a parliamentary private secretary (PPS) for health.
The 43-year-old also told MPs about the challenges faced by young people, saying that "the greatest tragedy of Britain today is that the next generation, for the first time in our modern history, face worse prospects than the last."
He said that young people stepped up during Covid, praising how "the generation least at risk gave up the most to help the rest of us keep safe".
But Streeting said they had been repaid by the government "shortchanging them on their education, layering on debt, making it harder to get on the housing ladder, failing to protect them from the AI jobs apocalypse".
"Millions of young people who work hard and do the right thing cannot see path to home ownership or security," he said, adding this means many are "postponing adulthood".
Streeting also made the case for a "new special relationship" with Europe, saying: "It's even more clear we would have been better off leading Europe than leaving the EU."
He concluded: "The Labour Party was elected to deliver real change. We still can."
Last week, a number of ministers stepped down following the poor election results in England, Wales and Scotland.
Josh Simons, the MP for Makerfield, also resigned, in order to provide a potential path back to parliament for Greater Manchester mayor Andy Burnham, who is now contesting the seat in a by-election.
Both Burnham and Streeting have made clear they would stand in a potential Labour leadership contest.
Four junior ministers and six ministerial aides quit on Monday and have since been replaced, as nearly 90 Labour MPs publicly urged Sir Keir to either resign immediately or draw up an exit timetable.
However, more than 150 MPs have come out in support of the PM or said it is not the right time for a leadership contest.
Sir Keir focused on tackling the cost of living at PMQs on Wednesday, part of a slew of announcements Downing Street has been making since his reset speech on Monday last week.
Reacting to Streeting's resignation speech, Education Secretary Bridget Phillipson told Radio 5 Live she believed Sir Keir should lead the Labour Party into the next election.
"I agree we've got a huge fight on our hands," she said.
"What I think is a shame is that Wes is now on the backbenches making that argument rather than serving in cabinet, because he's really talented and he's got so much to offer."
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