The former senator and actor died after a recurrence of lymphoma, his family said in a statement Sunday. He was 73 years old.
"It is with a heavy heart and a deep sense of grief that we share the passing of our brother, husband, father, and grandfather who died peacefully in Nashville surrounded by his family," the statement read.
"Our nation has lost a servant, Tennessee has lost a son, and our family has lost its rock."
Thompson was barely 30 years old when he became minority counsel to the Senate Watergate Committee in its investigation of the Watergate scandal
He wrote a book chronicling his experiences titled "At That Point in Time: The Inside Story of the Senate Watergate Committee."
A few years later, in 1978, Thompson took on the corruption case that would eventually launch his acting career.
Marie Ragghianti, who was fired as chair of the Tennessee Parole Board, hired Thompson to represent her in a wrongful termination case against Gov. Ray Blanton.
The case revealed a bribery scheme in which two of the governor's aides received money in exchange for granting paroles.
Ragghianti won her case and was reinstated. And Thompson was on his way to a decades-long acting career.
Hollywood and Washington
In 1985, Thompson made his acting debut in the film "Marie: A True Story," about his former client Ragghianti. Thompson played himself.
Then came several roles in the 1990s: "The Hunt for Red October," "Die Hard 2." and "In the Line of Fire."
But the attorney-turned-actor had his sights set on Washington. In 1994, he won a special election to fill Al Gore's vacant U.S. Senate seat.
Thompson was re-elected for a full term in 1996, and announced in 2002 he would not run for re-election.
'Law & Order' and the presidency
It was time for Thompson to get back to acting.
In the 2000s, Thompson became known as District Attorney Arthur Branch on NBC's "Law & Order."
He revealed in 2007 that he was diagnosed with non-Hodgkin's lymphoma. A few months later, he told Jay Leno that he was running for president.
But that candidacy was short lived. He dropped out after four months.
A lasting legacy
Renny Harlin, who directed "Die Hard 2," described Thompson as "a gentle giant whose loss is a tremendous one for both entertainment and politics."
"Fred was a sweet, funny and fiercely intelligent guy with a gentle heart -- a bear of a man who was warm and considerate towards all those around him." Harlin said.
He said Thompson "anchored 'Die Hard 2' with his powerful presence in the air traffic control tower."
"I¹m lucky to have known him," Harlin said.
U.S. Sen. Lamar Alexander of Tennessee, whom Thompson worked for as a special council in 1980, also said Thompson had a special charisma.
"Very few people can light up the room the way Fred Thompson did," Alexander tweeted. "He was my friend for nearly fifty years. I will miss him greatly."