Inouye also served as chairman of the committee that investigated the Iran-Contra arms and money affair, which rocked Ronald Reagan's presidency.
A quiet but powerful lawmaker, Inouye ran for Senate majority leader several times without success. He gained power as a member of the Senate Appropriations Committee and chairman of the defense appropriations subcommittee before Republicans took control of the Senate in 1994.
When the Democrats regained control in the 2006 elections, Inouye became chairman of the Senate Commerce Committee. He left that post two years later to become chairman of the powerful Senate Appropriations Committee.
Inouye also chaired the Senate Indian Affairs Committee for many years. He was made an honorary member of the Navajo nation and given the name "The Leader Who Has Returned With a Plan."
In 2000, Inouye was one of 22 Asian-American World War II veterans who belatedly received the nation's top honor for bravery on the battlefield, the Medal of Honor. The junior senator from Hawaii at the time, Daniel Akaka, had worked for years to get officials to review records to determine if some soldiers had been denied the honor because of racial bias.
Inouye's first political campaign in 1954 helped break the Republican Party's political domination of Hawaii. He was elected to the Territorial House of Representatives, where he served as majority leader. He became a territorial senator in 1958.
Inouye was serving as Hawaii's first congressman in 1962, when he ran for the Senate and won 70 percent of the vote against Republican Benjamin Dillingham II, a member of a prominent Hawaii family.
He is the last remaining member of the Senate to have voted for the Civil Rights Act of 1964.
"He served as a defender of the people of this country, championing historic changes for civil rights, including the equal rights of women, Asian-Americans, African-Americans and Native Hawaiians," said a visibly emotional Sen. Daniel Akaka, his longtime Hawaii colleague. "It is an incredible understatement to call him an institution, but this chamber will never be the same without him."
In 1968, President Lyndon Johnson urged Vice President Hubert Humphrey, who had won the Democratic nomination for president, to select Inouye as his running mate. Johnson told Humphrey that Inouye's World War II injuries would silence Humphrey's critics on the Vietnam War.
"He answers Vietnam with that empty sleeve. He answers your problems with (Republican presidential candidate Richard) Nixon with that empty sleeve," Johnson said.
But Inouye was not interested.
"He was content in his position as a U.S. senator representing Hawaii," Jennifer Sabas, Inouye's Hawaii chief of staff, said in 2008.
Inouye reluctantly joined the Watergate proceedings at the strong urging of Senate Democratic leader Mike Mansfield. The panel's investigation of the role of the Nixon White House in covering up a burglary at Democratic National Committee headquarters at the Watergate in June 1972 ultimately prompted the House to initiate impeachment proceedings against Nixon, who resigned before the issue reached a vote in the House.
In one of the most memorable exchanges of the Watergate proceedings, an attorney for two of Nixon's closest advisers, John Ehrlichman and Bob Haldeman, referred to Inouye as a "little Jap."
The attorney, John J. Wilson, later apologized. Inouye accepted the apology, noting that the slur came after he had muttered "what a liar" into a microphone that he thought had been turned off following Ehrlichman's testimony.
After the hearings, Inouye said he thought the committee's findings "will have a lasting effect on future presidents and their advisers. It will help reform the campaign practices of the nation."
He achieved celebrity status when he served as chairman of the congressional panel investigating the Iran-Contra affair in 1987. That committee held lengthy hearings into allegations that top Reagan administration officials had facilitated the sale of weapons to Iran, in violation of a congressional arms embargo, in hopes of winning the release of American hostages in Iran and to raise money to help support anti-communist fighters in Nicaragua.