Boris Johnson's Tory government was accused of treating the North with "contempt" after a bitter row erupted over proposed coronavirus lockdown restrictions.
Greater Manchester Mayor Andy Burnham said the North was "fed up of being pushed around", claiming the region was being treated "as the canaries in the coalmine" for an experimental regional lockdown strategy.
But the Government's own top scientific advisors have told him such a strategy has no guarantee of success, claimed Mr Burnham, and will result in job losses and hardship.
He said: "They are asking us to gamble our residents' jobs, homes and businesses and a large chunk of our economy on a strategy that their own experts tell them might not work. We would never sign up for that."
The Government has been pushing for the region's politicians to accept Tier 3 measures which would include the closure of pubs and bars unless they could operate as restaurants, as the north of England has among the highest infection rates in the UK.
But local MPs and council chiefs lined up to criticise the plan and the way it has been handled by Number 10 and the Department of Health and Social Care, with no decision yet announced on whether the Manchester region will face the top tier measures.
A key sticking point is the extra funding that would be made available to Greater Manchester if harsher lockdown measures are imposed.
A clearly angry Mr Burnham said measures proposed by Whitehall go "way beyond" the closure of pubs.
He said: "It is wrong to place some of the poorest parts of England in a punishing lockdown without proper support for the people and businesses affected.
"Last night the deputy chief medical officer told the leaders that to bring the infection rates down any regional lockdown would require widespread closures way beyond pubs to stand any real chance of working."
Mr Burnham suggested that the deputy chief medical officer, Professor Jonathan Van-Tam, had indicated that a nationwide lockdown was the "only certain thing to work".
He said: "But the Government told us this morning it is unwilling to do that because of the damage it will do to the national economy.
"And yet that is what they want to impose on the North West.
"So that was our conclusion from the Number 10 meeting this morning: they are willing to try and sacrifice jobs and businesses here to try and save them elsewhere."
Mr Burnham spoke outside at a press briefing in central Manchester, which quickly attracted onlookers and earned him cheers and applause as a small crowd gathered, as he berated the Government.
He suggested a national "circuit-break" or limited national lockdown, is preferable to a regional lockdown for the North.
He added: "We have to protect the health of the nation but let's do it as one nation, and not make the North of England the sacrificial lamb for an ill-thought-through Downing Street policy which doesn't make sense in the real world.'
"People are fed up of being treated in this way, the North is fed up of being pushed around.
"We aren't going to be pushed around anymore."
More talks between northern leaders and the Government are expected on Friday.