Karras struggled in the beginning at Iowa, with classwork, homesickness and with his coach, Forest Evashevski. He was a pledge at Sigma Nu fraternity during his first year in school. Alex probably would have left Iowa had he not befriended a Greek theater owner, Ernie Pannos, as well as fellow players Cal Jones and Bob Commings. Karras' sophomore year with Iowa in 1955 got off to a rocky start when he showed up for practice twenty pounds overweight. Karras was also hampered that season by a cracked ankle bone. After being disappointed at not getting to play in the season finale, Karras threw a shoe at Evashevski and quit the team. Karras did not earn a football letter for the 1955 season.

Iowa's final regular season game in 1956 was against Notre Dame, which Iowa won, 48-8. Karras called it his biggest college win, saying, "The Karrases have always had a rivalry with Notre Dame. The school was just 60 miles down the road from our home and we wanted to beat 'em at anything." However, after the game, Karras got into a physical battle with Evashevski. Karras did not enjoy his trip to the Rose Bowl, either. "Pasadena was the most boring town I’ve ever been in," said Karras. Karras helped the Hawkeyes win the 1957 Rose Bowl over Oregon State, 35-19. He was a first team All-American in 1956.

Before his NFL career got under way, Karras signed a contract as a professional Wrestler on December 13, 1957, earning $25,000 during the six-month off-season. Karras was drafted in the first round of the NFL Draft by the Detroit Lions in 1958. He signed with the Lions, spurning an offer from the Canadian Football League's Winnipeg Blue Bombers. He quickly became one of the dominant defensive tackles in the NFL, playing for 12 seasons (1958–1962, 1964–1970) with the same team.

From 1958 to 1970, the Lions were over .500 six of the 13 years, making the playoffs only once, 1970, with a 10-4 win-loss record, Karras' final year. Aside from 1970, their best years were 1962 (11-3) and 1969 (9-4-1). In 1962, the Lion defense allowed 177 points (12.6 points/game), in 1969 188 points (13.4 points/game), and in 1970 202 points (14.4 points/game), for all three years the second-least in the NFL, thanks in large part to a tough and rugged defensive line led by Karras. Karras was called an "iron man", since he missed only one game due to injury in his 12 NFL seasons and his 161 games played are the 15th most in Lions history. He made the Pro Bowl four times, and the Hall of Fame named him a member of the 1960s All-Decade team. The Professional Football Researchers Association named Karras to the PRFA Hall of Very Good Class of 2006

On January 7, 1963, Karras's ownership in Detroit's Lindell AC Bar became a source of controversy when league officials urged him to sell his financial interests in the place because of reports of gambling and organized crime influence. After first threatening to retire rather than give it up, Karras admitted placing bets on NFL games and was suspended by the league, along with Green Bay Packers' running back Paul Hornung, for one season (1963). During his exile, Karras returned to pro wrestling, taking on such memorable characters as Dick the Bruiser. He was reinstated, along with Hornung, on March 16, 1964 by NFL commissioner Pete Rozelle. Upon returning to action in 1964, Karras once refused when an official asked him to call the pregame coin toss. "I'm sorry, sir," Karras replied. "I'm not permitted to gamble." During his first year back, player discontent with head coach George Wilson resulted in Karras asking to be traded. However, the Lions settled the issue when they fired Wilson after the 1964 NFL season.

Besides being one of the subjects of George Plimpton's nonfiction book Paper Lion (published in 1966), he was one of the two principal subjects of Plimpton's follow-up book, Mad Ducks and Bears (1973) (fellow Detroit Lion John Gordy was the "bear" to Karras' "mad duck.") Karras named one of his sons after Plimpton. During his last years as a Detroit Lion, Karras wrote a journal of his experiences that was published in the Detroit Free Press. He subsequently wrote a memoir, Even Big Guys Cry (1978), and a novel, Tuesday Night Football (1991).

In 1968, he made his film debut playing himself in the film adaptation of George Plimpton's nonfiction Sports book Paper Lion. As in Plimpton's book, Karras delights his teammates with impromptu monologues about a fanciful past, including his marriage to Hitler.

Following his release by the Lions in 1971 he made several appearances on The Tonight Show Starring Johnny Carson and also played a bit part in The Mary Tyler Moore Show, appearing in the farewell party scene where Rhoda moves back to New York (1972). Karras soon began acting on a full-time basis, playing a Tennessee boy turned Olympic Weight Lifter named Hugh Ray Feather in 1973's The 500 Pound Jerk. He played a hulking villain who menaced Clint Walker in the ABC TV film Hardcase. A minor but memorable role came one year later in the western parody Blazing Saddles (1974): the very strong and slow-witted thug Mongo, who rode into town on a huge brahman (marked with "yes" and "no" passing signals), knocked out a horse with one punch, and famously responded to a question from Sheriff Bart with, "Don't know..." (looking straight into the camera) "...Mongo only pawn in game of life." That same year, he was quickly brought in by ABC to replace Fred Williamson as a commentator for the network's Monday Night Football. He served three years in that role until leaving after the 1976 NFL season, with his most memorable comment coming in his first game, when he joked that bald Oakland Raiders' lineman Otis Sistrunk, who never attended college, was from "the University of Mars".

In 1972, Karras hosted a local weekly football program for Windsor, Ontario CBC affiliate CKLW-TV, The Alex Karras Football Show; his program generally preceded the CBC's Wednesday night CFL telecasts.

Karras' television appearances included guest roles on Daniel Boone in the episode "The Cache", M*A*S*H in the episode "Springtime", The Odd Couple and a brief run on Match Game '75. He also signed on to play the character "Super Jock" in commercials for a line of Sports action toys named Super Jock, produced by Schaper (1975). In 1977, he was cast in the lead of the TV movie Mad Bull.

In 1979, he had the role of Hans "Potato" Brumbaugh, a potato farmer, on the TV miniseries Centennial. He was known for his humorous endorsement of La-Z-Boy recliners, in an ad campaign which also featured NFL greats such as Miami Dolphins Coach Don Shula, and New York Jets legend Joe Namath. In the 1980s, Karras had memorable success in the TV sitcom Webster, playing George Papadapolis, the title character's adoptive father, in a role that showcased his softer side. His real-life wife, Susan Clark, played his fictional wife in the series; Karras and Clark produced the series through their Georgian Bay Entertainment production company. The two met in 1975 while filming the made-for-television biopic Babe for CBS.

Karras was married twice. He married Joan Jurgensen in 1958, with whom he had five children. The marriage ended in divorce in 1975. He married Actress Susan Clark on March 21, 1980, and they had a daughter together.

Karras returned to acting with roles that included playing Sheriff Wallace in Porky's (in which his wife, Susan Clark, also starred), and as western settler Hans Brumbaugh in Centennial. He played James Garner's closeted gay bodyguard in the 1982 Blake Edwards' film Victor Victoria. Karras played a darker role as Hank Sully, the right-hand-man of villain Jake Wise (played by James Woods) in the 1984 film, Against All Odds. Karras' most memorable role was in the 1975 made-for-TV movie Babe, where he played the hulking ex-wrestler George Zaharias, loyally caring for his cancer-stricken wife, the legendary athlete Babe Didrikson Zaharias.

In conjunction with the 100 Years of Hawkeye Football celebration in 1989, Iowa Hawkeye fans selected an all-time team. The squad featured 11 players on offense and defense, two kickers, and 15 special-mention players who received strong fan support. Alex Karras was voted to the team as a defensive lineman. Karras was elected to the Iowa Sports Hall of Fame in 1977 and the College Football Hall of Fame in 1991.

Karras also worked briefly as a football coach in 2007 and 2008. He worked for the SIL as an assistant coach to Bob Lombardi. He owned an ice cream parlor in Surfside Beach, South Carolina called The Cow.

On October 8, 2012, it was revealed by friend Tom McInerney that Karras had been diagnosed with kidney failure. He was treated at the Saint John's Health Center in Santa Monica, California, before being released into hospice care. After returning to his Los Angeles home with family, Karras died in the morning hours of October 10.

On December 12, 2014 the Big Ten Network included Karras on "The Mount Rushmore of Iowa Football", as chosen by online fan voting. Karras was joined in the honor by Nile Kinnick, Chuck Long and Tim Dwight.