Westminster has "failed the North", Andy Burnham will say as he formally launches his campaign to be mayor of Greater Manchester.
The former cabinet minister, who has been an MP since 2001, will say he is ready to leave the Commons in order to tackle the North-South divide and make Manchester a "beacon of social justice".
In a speech in Salford, Burnham will set out his plans for an integrated health and care service, measures to buy homes off absentee landlords and proposals for a "revolution" in technical education.
He will also challenge Chancellor George Osborne to act on his Northern Powerhouse agenda by prioritising the trans-Pennine high-speed rail link instead of London's Crossrail 2.
Burnham, who will face opposition for the Labour nomination for the 2017 contest from interim mayor Tony Lloyd and former minister Ivan Lewis, will stress that the job requires "Cabinet-level experience" - something his rivals lack.
The shadow home secretary will say: "Centuries of our Westminster system have made England a very unequal country. Put bluntly, Westminster has failed the North. It has left us with an uneven share of resources, power and life chances.
"The London perspective on life dominates the political debate and does not do justice to the challenges that people here face.
"In my 15 years in Parliament, I have consistently challenged that. But now I want to go a step further. I am ready to leave Westminster and devote myself to this new task of rebalancing our country from South to North."
The Leigh MP, a former health secretary, has long favoured the idea of integrating health and social care and will seek to implement that idea in Manchester.
"There is one way that Greater Manchester can stand out as a beacon of social justice perhaps more than any other - and that is how we care for older or vulnerable people," he will say.
"As mayor, I will make it my mission to build here the country's first fully integrated National Health and Care Service."
Under his plans for a "revolution in technical education", he will spell out an ambition of creating a quality apprenticeship place for every young person who gets the grades and a new support scheme for people who want to start up their own business.
Setting a goal of ensuring an affordable home for everyone to rent or own and an end to homelessness in the region, Burnham will pledge to use the mayor's housing fund to buy out absentee private landlords.
A Greater Manchester rent-to-own scheme would build new homes and help people onto the housing ladder.
In a challenge to the Chancellor, he will say: "We have put up with outdated, overcrowded rail services for too long. So I will make it my business to ensure the Government commits to major investment in brand new high-speed East-West rail across the North.
"Let me be clear: this is the top priority for the country, not Crossrail 2. If George Osborne is serious about a Northern Powerhouse, he must put his money where his mouth is."
Burnham will encourage Labour's "biggest hitters" to stand in elections for the new generation of "metro mayors" with devolved powers.
Shadow cabinet minister Luciana Berger has confirmed she is weighing up whether to stand for the role in the Liverpool city region.
Burnham will say: "Let Greater Manchester lead the campaign for a more equal England. If we lead the way, we can in time build a cabinet of the North that will make its voice heard loud and clear and rebalance this country of ours."