Senator Kennedy's widow, Vicki, and other members of the family shook hands with many of the mourners.
After the public paid their respects in Boston, a three-hour memorial service described as a "celebration of life" began at the JFK library on Friday evening.
Speakers included Vice-President Joe Biden; Senators John McCain, Orrin Hatch, John Kerry and Christopher Dodd; and niece Caroline Kennedy, daughter of President John F Kennedy.
Also present was Arnold Schwarzenegger, Republican governor of California and former Hollywood actor who married into the Kennedy family.
Others at the wake-style event included Sinn Fein leaders Martin McGuinness and Gerry Adams, who worked with Senator Kennedy during the Northern Ireland peace process.
After a choral rendition of "God Bless America", family members and friends paid tribute to the senator.
Joseph Kennedy, son of the late Robert Kennedy, joked that the only time he beat his uncle in a sailing race was when the senator's boat started to sink.
Bobby Kennedy Jnr: Edward Kennedy believed that "every individual counted"
Mr Biden said Senator Kennedy became a "big brother" to him when he joined the senate 36 years ago, and encouraged him to keep his seat after his wife and daughter died in a car accident.
President Barack Obama is expected to address a funeral Mass for Mr Kennedy at Our Lady of Perpetual Help Basilica in Boston on Saturday, before his burial that evening.
Mr Kennedy's death on Tuesday prompted a flood of tributes from across the US and around the world.
British Prime Minister Gordon Brown wrote in the Boston Globe newspaper that Mr Kennedy "is rightly mourned as one of America's greatest advocates of social justice... as a great internationalist who inspired social progress in every country."
In the US, Mr Kennedy's death has been seen as the end of an era.
The charismatic senator had long been the leader of one of America's great political dynasties, following the assassinations of his brothers in 1963 and 1968.
In a televised tribute on Wednesday, Mr Obama said Mr Kennedy had achieved "extraordinary good" and was "one of the most accomplished Americans ever to serve our democracy".
But others have noted that his legacy of public service was counter-balanced by heavy drinking in his early years - and the death of a female companion, Mary Jo Kopechne, in 1969 when he drove off a bridge at Chappaquiddick in Massachusetts and fled the scene.
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