"We thank everyone who gave him care and support over this last year, and everyone who stood with him for so many years in his tireless march for progress toward justice, fairness and opportunity for all."
Kennedy - more widely known as "Ted" or "Teddy" - was diagnosed with brain cancer in May last year.
Rob Reynolds, Al Jazeera's senior Washington correspondent, said: "This is really the end of an era in American political history that began long ago with the rise of the Kennedy family to prominence in American politics.
"Ted Kennedy himself was a very accomplished legislator. He championed a number of progressive causes, including immigration, right to abortion, gun control and others."
Kennedy also helped draft legislation to overhaul the $2.5 trillion US healthcare system.
He wrote in the Boston Globe newspaper in May: "I've benefitted 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 short-changes millions of Americans."
Reynolds said: "He also was instrumental in the long, long fight to reform the American healthcare system, so it is somewhat ironic that, as the debate over healthcare reform grows very heated, Ted Kennedy's voice is silenced."
Barack Obama, the US president, said that he was "heartbroken" by the death of someone he considered a "dear friend".
"As we mourn his loss, we rededicate ourselves to the causes for which he so dutifully dedicated his life"
Harry Reid, US senate Democratic leader
"I valued his wise counsel in the senate, where, regardless of the swirl of events, he always had time for a new colleague. I cherished his confidence and momentous support in my race for the presidency," he said in a statement.
"And even as he waged a valiant struggle with a mortal illness, I've profited as president from his encouragement and wisdom.
Harry Reid, the senate Democratic leader, said in a statement that the Kennedy family and the 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."
Kennedy became known as one of Washington's most effective senators, crafting legislation by working with politicians and presidents of both parties, often finding unlikely allies.
Across the aisle
A 2009 survey by The Hill, a publication following politics on Capitol Hill, found that senate Republicans believed Kennedy was the chamber's easiest Democrat to work with and the most bipartisan.
|Barack Obama, left, said that he valued
Kennedy's 'wise counsel' [AFP]
"I am a Republican and he was a Democrat, but we were friends," Jack Burkman, a Republican party strategist, said.
"He was one of the few people in the United States senate who could genuinely reach across the aisle and bring Democrats and Republicans together," he told Al Jazeera from Los Angeles.
"There are a lot of people who claim to be able to do this, but there really are only two or three.
"I think America needs more Ted Kennedys, people who believe passionately in what they believe in."
The younger brother of JFK and Robert F Kennedy, the assassinated former senator, Edward Kennedy was serving his ninth term as a Democratic senator.
Kennedy was elected to the senate in 1962, while his brother John was still president, and served longer than all but two senators in history.