She was 55.
Prime Minister Tony Blair, who made Mowlam his top Northern Ireland official in 1997, described her as "one of the most remarkable and colourful personalities ever to come into politics. Great company, utterly irreverent, full of life and fun".
Observers of the tense negotiations that led to the 1998 Good Friday accord, which revived Catholic-Protestant power-sharing in the British-governed province, cited Mowlam's approachability as a key factor.
Famously informal, she kicked off her shoes in meetings, threw her wig - a product of her battle with a brain tumor - on the table at a moment of high tension and was caught on tape calling Sinn Fein negotiator Martin McGuinness "babe".
In 1998, she met with Protestant paramilitary inmates inside the Maze prison, overcoming their opposition to peace talks.
Although some Protestant politicians felt Mowlam favoured the Irish nationalist cause, her tenure appeared to encourage the Irish Republican Army-tied Sinn Fein Party to participate in the peace process.
"I certainly had a sense that this was someone who wanted to be part of change ... I think she wanted to make a contribution and I think she made a very powerful and worthwhile contribution," McGuinness told British Broadcasting Corp television.
Former US president Bill Clinton said Mowlam's "persistence, toughness and good humour were legendary".
"All of us who worked to support peace in Northern Ireland owe her our gratitude," Clinton said.
Former US senator George Mitchell, who chaired the talks that led to the Good Friday agreement, said Mowlam had "helped reinvigorate the process and bring it to a successful conclusion".
Mowlam, who had recently suffered balance problems as a result of radiotherapy treatments for her brain tumour, hit her head in a fall last month, a family friend told The Associated Press, requesting that he not be identified.
She was admitted to King's College Hospital in London, but failed to regain consciousness and was transferred last week to a hospice in Canterbury, southern England.
Care providers followed her request that she not be kept alive artificially and withdrew life support earlier this week, the friend said.
Frank and brave
Mowlam died at 8.10am (0710 GMT), family spokesman Brian Basham said in a statement.
First elected to Parliament in 1987, Marjorie Mowlam -universally known as Mo - was one of Britain's most popular politicians, admired for her willingness to speak frankly, her bravery in fighting the brain tumour and her role in
Northern Ireland's peace process.
She was appointed Northern Ireland secretary soon after Blair's Labour Party came to power in 1997, and served until 1999.
Mowlam is survived by her husband, Jon Norton. A private funeral will be followed by a memorial event in a few months, Basham said.