Karras, who also starred in the television sitcom "Webster," had been suffering from kidney failure, dementia, heart disease and cancer in recent years, his family said.
Earlier this year, Karras joined a class-action lawsuit by former National Football League players who said the league did not do enough to protect them from head injuries. The suit said Karras had sustained repeated head trauma.
His lawyer, Craig Mitnick, said Karras was surrounded by family when died at his home in Los Angeles.
"He suffered from dementia for the last decade of his life," Mitnick said. "He had lost his zest for life. He had suffered though dementia, he had suffered through cancer, his body just eventually gave way.
"He was such a strong, charismatic man. The dementia took that energy away."
While he made hundreds of tackles on the football field, Karras' most memorable take-down occurred on a movie screen when he played Mongo, a dull-witted brute who knocked down a horse in Mel Brooks' 1974 comic Western film, "Blazing Saddles."
Karras grew up in Gary, Indiana, and was an All-American at the University of Iowa. He joined the Lions in 1958 and became one of the best defensive tackles in the NFL. He was an All-Pro selection four times but his irreverent nature often led to conflicts with his coaches and he missed the 1963 season when he was suspended for gambling.
After returning to football, Karras represented the Lions at the pre-game coin flip to determine which team would kick off. When the referee told him to call heads or tails, Karras responded, "I'm sorry, sir, I'm not permitted to gamble."
Despite being one of the best players of his time, Karras was never inducted into the NFL Hall of Fame.
Karras was known to teammates as "The Godfather" - a glib, wise-cracking figure who enjoyed big cigars, even in the shower.
He was a key figure in "Paper Lion," a look at the 1963 Detroit team by writer George Plimpton, who tried out for the team to see what it would be like for an average person. Karras and Plimpton became friends and Karras named one of his sons after the writer.
"While his legacy reached far beyond the gridiron, we always will fondly remember Alex as one of our own and also as one of the best to ever wear the Honolulu blue and silver," said Lions President Tom Lewand.
After 12 seasons the Lions cut Karras in 1971 and he became a commentator on ABC's "Monday Night Football" broadcast for three years.
His family said Karras was always interested in acting and he played himself in a movie version of "Paper Lion." His biggest acting success came as a star of the 1980s sitcom "Webster," joining his real-life wife, Susan Clark, in playing a white couple who adopt a black child played by Emmanuel Lewis.
In addition to the scene in which he cold-cocked the horse, "Blazing Saddles" provided Karras with line often quoted by the movie's fans - "Mongo only pawn in game of life."
Karras' other movie roles included a sheriff in "Porky's," a gay bodyguard in "Victor/Victoria" and the husband of golf star Babe Zaharias, who was portrayed by Clark, in "Babe."
His wit made Karras a popular guest on Johnny Carson's "Tonight" show.
Before his NFL career and during his suspension, Karras was also a professional wrestler.
Karras, who had six children, wrote about his life in "Even Big Guys Cry" and "Alex Karras: My Life in Football, Television & Movies."
(Additional reporting by Christine Kearney in New York; Editing by Doina Chiacu)
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