Kalil has been selected to the Pro Bowl in 2009, 2010, 2011, 2013, and 2015.
Kalil went to Servite High School in Anaheim, California, where he was teammates with future New England Patriots wide receiver Matthew Slater.
Kalil attended the University of Southern California, where he played for the USC Trojans football team. He was a 2005 Sports Illustrated All-American, and won the USC Trojans' Bob Chandler Award in 2005 and Courage Award in 2004 and on the watch list for the Lombardi Award.
Kalil was on the official watch list for the Rimington Trophy for the top college football center and the Outland Trophy watch list for the best lineman. He was named to the 2005 and 2006 Pac-10 coaches and Rivals.com All-Pac-10 team First Team. He was a Pro Football Weekly All-American choice and a Rivals.com second-team All American and SI.com honorable mention All-American.
Kalil was voted "lineman of the year" by his Trojans teammates and won the 2006 Morris Trophy. Kalil was invited to play in the Senior Bowl prior to the 2007 NFL Draft.
Kalil ran the 40-yard dash in 4.94 seconds at the 2007 NFL Combine and bench pressed 225 pounds 34 times. His performances at the combine and the Senior Bowl impressed scouts and led many analysts to project he would be selected in the first or second round of the 2007 NFL Draft.
Pre-draft predictions turned out to be correct, as Kalil was selected in the second round of the draft with the 59th pick by the Carolina Panthers. He was the first center to be selected in the 2007 draft and joined his teammate from the USC Trojans, Dwayne Jarrett, who the Panthers also selected in the second round.
In 2007, Kalil started three games at center.
In 2008, Kalil was named the full-time starter at center. He started in all 12 games that he appeared, missing four games due to injury.
In 2009, Kalil was voted second-alternate to the 2010 Pro Bowl. He later was given a spot due to an injury by the first alternate.
In 2010, Kalil was named a first alternate, but was added to the roster after Giants center Shaun O'Hara pulled out.
In 2011, Kalil received a franchise tag from the Carolina Panthers.
On August 19, 2011, the Panthers signed Kalil to a six-year $49 million deal, making him the highest paid center in NFL history. He was selected to the Pro Bowl as the starting center of the NFC team.
On February 7, 2016, Kalil was part of the Panthers team that played in Super Bowl 50. In the game, the Panthers fell to the Denver Broncos by a score of 24–10.
It was announced on December 23, 2015 that Kalil was one of ten players on the Carolina Panthers voted into the 2016 Pro Bowl, making it Kalil's fifth appearance. Kalil could not play in the Pro Bowl due to the Panthers appearance in Super Bowl 50. For the 2015 season, PFF rated Kalil as the third-best run-blocking center in the NFL. He was ranked 79th on the NFL Top 100 Players of 2016.
On June 6, 2016, Kalil signed a two-year extension with the Panthers. Kalil had been dealing with a shoulder injury for several weeks before leaving the Week 11 game against the New Orleans Saints. He was placed on injured reserve on November 29, 2016, ending his season.
Kalil's father, Frank, played football for the University of Arkansas and the University of Arizona. He was drafted by the National Football League Buffalo Bills in 1982 and later played in the United States Football League until 1984. His mother, Cheryl (née Van Cleave), was Miss California in 1981. He is of Lebanese and Mexican heritage, and has two siblings: brother Matt, is a former starting offensive tackle at USC, was drafted fourth overall by the Minnesota Vikings in 2012, and is now an offensive tackle with the Carolina Panthers. They will be the third set of brothers to play on the same offensive line in the NFL and the first set of brother to do it in 24 years.Their sister Danielle sang the national anthem at the Vikings–Panthers game, which featured both her brothers, on October 13, 2013.
Kalil and his wife, Natalie, a former USC cheerleader, have two daughters.
Kalil has interests in the film industry, having made claymation films as a child and worked with fellow USC-alumnus Will Ferrell on a football training spoof for the NFL Network. In June 2016, Deadline.com announced Kalil will serve as an executive producer along with Dwayne Johnson producing Sony Pictures film "Son of Shaolin." Kalil financed production of the underlying graphic novel through his Strange Turn Entertainment banner.