"Edward M. Kennedy, the husband, father, grandfather, brother and uncle we loved so deeply, died late Tuesday night at home in Hyannis Port (Massachusetts)," the Kennedy family said in a statement.
One of the most influential and longest-serving senators in U.S. history -- a liberal standard-bearer who was also known as a consummate congressional dealmaker -- Kennedy had been battling brain cancer, which was diagnosed in May 2008.
"We've lost the irreplaceable center of our family and joyous light in our lives, but the inspiration of his faith, optimism, and perseverance will live on in our hearts forever," the family statement said.
"He loved this country and devoted his life to serving it. He always believed that our best days were still ahead, but it's hard to imagine any of them without him," the family added.
His death marked the twilight of a political dynasty and dealt a blow to Democrats as they seek to answer President Barack Obama's call for an overhaul of the healthcare system. Kennedy had made healthcare reform his signature cause.
Senate Democratic leader Harry Reid said in a statement the Kennedy family and Senate "have together lost our patriarch."
"As we mourn his loss, we rededicate ourselves to the causes for which he so dutifully dedicated his life."
Known as "Teddy," he was the brother of President John Kennedy, assassinated in 1963, Senator Robert Kennedy, fatally shot while campaigning for the 1968 Democratic presidential nomination, and Joe Kennedy, a pilot killed in World War Two.
When he first took the Senate seat previously held by John Kennedy in 1962, he was seen as something of a political lightweight who owed his ascent to his famous name.
Yet during his nearly half century in the chamber, Kennedy became known as one of Washington's most effective senators, crafting legislation by working with lawmakers and presidents of both parties, and finding unlikely allies.
At the same time, he held fast to liberal causes deemed anachronistic by the centrist "New Democrats," and was a lightning rod for conservative ire.
He helped enact measures to protect civil and labor rights, expand healthcare, upgrade schools, increase student aid and contain the spread of nuclear weapons.
"There's a lot to do," Kennedy told Reuters in 2006. "I think most of all it's the injustice that I continue to see and the opportunity to have some impact on it."
After Robert Kennedy's death, Edward was expected to waste little time in vying for the presidency. But in 1969, a young woman drowned after a car Kennedy was driving plunged off a bridge on the Massachusetts resort island of Chappaquiddick after a night of partying.
Kennedy's image took a major hit after it emerged he had failed to report the accident to authorities. He pleaded guilty to leaving the scene and received a suspended sentence.
Kennedy eventually ran for his party's presidential nomination in 1980 but lost to then-President Jimmy Carter.
His presidential ambitions thwarted, Kennedy devoted himself to his Senate career.
A 2009 survey by The Hill, a Capitol Hill publication, found that Senate Republicans believed Kennedy was the chamber's easiest Democrat to work with and most bipartisan.
Republican Senator John McCain called Kennedy "the single most effective member of the Senate if you want to get results."
In January 2008, Kennedy endorsed Obama, who was serving his first term as a senator, for the Democratic presidential nomination. Many saw the endorsement -- Obama went on to win the nomination and the White House -- as the passing of the political torch to a new generation.
'LION' BATTLED ON
Kennedy had been largely sidelined in Congress since becoming ill. The "Lion of the Senate" began to use a cane and often looked tired and drained as he mixed work with treatment.
Yet colleagues and staff said he remained determined to fulfill what he called "the cause of my life," providing health insurance to all Americans. He helped draft legislation to overhaul the $2.5 trillion U.S. healthcare system.
Kennedy's interest in healthcare dated from his son's bout with cancer in the 1970s. More recently, he cited his own illness as he made a case for reform.
"I've benefited from the best of medicine, but I've also witnessed the frustration and outrage of patients and doctors alike as they face the challenges of a system that shortchanges millions of Americans," he wrote in a May 28, 2009, issue of the Boston Globe.
His charisma as "the last of the Kennedy brothers" was such that draft-Teddy drives were a feature of U.S. presidential election years from 1968 through the 1980s.
But he never fully escaped the cloud of the Chappaquiddick accident. A decades-long argument arose about whether he tried to cover up his involvement by leaving the scene while Mary Jo Kopechne's body remained submerged and whether police helped sweep such questions under the rug. All involved denied any cover-up.
Later crises involving younger Kennedys, notably the 1991 Palm Beach rape trial of his nephew, William Kennedy Smith, caught a bloated and weary-looking Uncle Ted in a media glare. Reports of heavy drinking and womanizing led to a public apology for "the faults in the conduct of my private life."
Kennedy was remarried soon after that to Victoria Reggie, a 38-year-old lawyer with two young children from her first marriage. He poured renewed energy into the Senate, where he would become the third-longest serving senator in history.
Even his Republican foes recognized Kennedy's dedication as he worked to protect civil rights, give federal help to the poor, contain the spread of nuclear weapons, raise the minimum wage, expand health coverage and improve America's schools.
Born on February 22, 1932, Edward Moore Kennedy was the last of four sons and five daughters born to millionaire businessman Joseph Kennedy, who would later be ambassador to Britain, and his wife Rose.
The Boston Irish family combined the competitive spirit of nouveau riche immigrants with acquired polish and natural charm. The sons were expected to mature into presidential timber and were groomed for that starting with the oldest, Joseph Jr., a bomber pilot who died in World War Two.
"I think about my brothers every day," Kennedy told Reuters. "They set high standards. Sometimes you measure up, sometimes you don't."
Like his brothers, Kennedy was known for his oratory, delivered in a booming voice at rallies, congressional hearings and in the Senate.
He drew praise from liberals, labor and civil rights groups and scorn from conservatives, big business and anti-abortion and pro-gun activists. His image was often used by Republicans in ads as a money-raising tool.
Tragedies dogged Kennedy throughout his life. They included a 1964 plane crash that damaged his spine and left him with persistent pain; bone cancer that cost son Teddy a leg; first wife Joan's battles with alcoholism that contributed to their divorce, and drug problems involving nephews, one of whom died of an overdose. His nephew, John Kennedy Jr., died in July 1999 when his small plane crashed into the ocean near Cape Cod.
In May 2008, Edward Kennedy collapsed at his Cape Cod home and was flown to hospital in Boston, where he was diagnosed with a malignant brain tumor. Brain cancer kills half its victims within a year.
Kennedy's illness kept him from attending the funeral of his sister, Eunice Kennedy Shriver, a leading advocate of the mentally disabled, who died on August 11 at the age of 88.
(Additional reporting by Thomas Ferraro; Editing by Peter Cooney)