Payne, the first black congressional member from New Jersey, died at St. Barnabas Hospital in Livingston, said his brother, William.
The 12-term member of the House had announced in February that he was undergoing treatment for colon cancer and would continue to represent his district. He was flown back home to New Jersey on Friday from Georgetown University Hospital as his health took a sudden turn for the worse.
He was first elected in 1988 after twice losing to former Rep. Peter Rodino, who retired in after 40 years in Congress.
Payne, often considered the most progressive Democrats in the state's delegation, was elected to a 12th term in 2010. He represented the 10th District, which includes the city of Newark and parts of Essex, Hudson and Union counties.
In Washington, he was remembered for his work as a defender of human rights, both at home and abroad.
President Barack Obama, who ordered flags lowered in Payne's honor, called him a "leader in US-Africa policy, making enormous contributions towards helping restore democracy and human rights across the continent."
Payne was a member of House committees on education and foreign affairs. He also had served as chairman of the House subcommittee on Africa, and had traveled many times to the continent on foreign affairs matters.
During an April 2009, mortar shells were fired toward Mogadishu airport as a plane carrying Payne took off safely from the Somali capital. Officials at the time said 19 civilians were injured in residential areas. Payne had met with Somalia's president and prime minister during his one-day visit to Mogadishu to discuss piracy, security and cooperation between Somalia and the United States.
He also had been the chairman of the Congressional Black Caucus and a congressional delegate to the United Nations.
At home he was remembered as a trailblazer for African-Americans, as an advocate for the underprivileged, and as a gentleman.
Newark Mayor Cory Booker called him a "a humble hero who lived an extraordinary life of contribution and distinction" and "a defender of and advocate for the rights, liberties, equal opportunities, and dignity of all people."
Born and raised in Newark, Payne came up through the ranks of Essex County politics. He earned a bachelor's degree from Seton Hall University in 1957 and taught in Newark schools for 15 years. He went on to become an insurance executive and member of the Newark City Council from 1982 until 1988. He also served as president of the national YMCA.
A public plaza between two government buildings in Newark now bears his name in tribute to his long career in public service.
Payne was a widower with three children and four grandchildren. His son, Donald Payne Jr., is a Newark city councilman. Services haven't been announced.
While Payne faced the prospect of a primary challenge from Newark Councilman Ronald C. Rice, his death will open the field in the heavily Democratic district.
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Associated Press writer Andrew Miga in Washington contributed to this report.
