In 2008, he won the Republican nomination, only to see his hopes dashed by the phenomenon that was Barack Obama and a crumbling USA economy.
"My deepest sympathies and respect go out to the family of Senator John McCain", he said. "Our hearts and prayers are with you!" he added. He said that "the nation mourns the loss of a great American patriot" and that the Senate is "keeping Cindy, the McCain family, all John's friends and staff, and the people of Arizona in our prayers at this tremendously hard time".
As the son of a naval officer, McCain and the family were constantly on the move. His wife and other family members were with him.
"At John's best, he showed us what that means".
And thought they were on opposite sides of the aisle, "We're like two brothers who were somehow raised by different fathers or something because of our points of view", Biden said.
McCain was born on August 29, 1936, at an American naval installation in the Panama Canal Zone - U.S. territory at the time - when his father was stationed there. Character. Courage. Integrity. Honour.
What happens to John McCain's Senate seat? His impact on America hasn't ended. He served Arizona for more than 30 years on Capitol Hill.
McCain found Putin's growing influence on the world stage particularly worrisome.
"I am lucky to count myself among those privileged enough to have known him".
Mr. Bush issued a statement hailing McCain as a "a man of deep conviction and a patriot of the highest order". He was a public servant in the finest traditions of our country.
John McCain was about more than politics. "God bless and thank you all".
McCain lost said election to former President Barrack Obama.
"Sen. John McCain was a maverick and a fighter, never afraid to stand for his beliefs".
"America will miss John McCain".
"No ma'am", McCain said, taking the microphone from her.
The Obamas shared their own lengthy message on Twitter too, praising his courage in both politics and the war, before sending their best wishes to Cindy and the rest of the senator's family.
The news comes not long after McCain made the decision to stop medical treatment after a year-long battle with brain cancer.
Dan Scavino, Trump's longtime social media director said the flags at the White House have been lowered to half-staff in honor of the late senator.
A police escort accompanied the hearse that carried his body, as a fiery sunset cast its last light over the rustic countryside McCain loved dearly, and local residents came bearing flowers for the late political titan. He put country before self.
It was just one of the many moves that earned McCain the "Maverick" moniker. "Few sacrificed more for, or contributed more to, the welfare of his fellow citizens - and indeed freedom-loving peoples around the world", he said in a statement. "This Congress, this country, mourn with them".
After Trump became president, McCain blasted what he called the president's attempts to undermine the free press and rule of law, and lamented the "half-baked, spurious nationalism" of the Trump era.
John McCain dies of brain cancer at 81
McCain was married to Carol Shepp from 1965 until 1980, when the two divorced and he married his second wife, Cindy Hensley. He was a courageous leader who served Arizona and the United States with tremendous pride, dignity and distinction.