Kalil attended Servite High School in Anaheim, California, where he played for the Servite Friars high school football team. He made the 2005 Cal-Hi Sports All-State Sophomore first team. As a junior in 2006, he made Cal-Hi Sports All-State first team, Cal-Hi Sports All-State Underclass first team, All-CIF Pac-5 Division first team, Los Angeles Times All-Star and All-Trinity League Co-Lineman of the Year. His 2007 senior season honors included Parade All-American, Super Prep All-American, Prep Star All-American, EA Sports All-American first team, USA Today All-USA second team, Scout.com All-American second team, ESPN 150, Super Prep Elite 50, Prep Star Dream Team, Super Prep All-Farwest, Prep Star All-West, Long Beach Press-Telegram Best in the West first team, Orange County Register Fab 15, Tacoma News Tribune Western 100, Cal-Hi Sports All-State first team, All-CIF Pac-5 Division first team, Los Angeles Times All-Star, Orange County Register All-Orange County first team and All-Trinity League Co-Lineman of the Year as a senior offensive and defensive lineman at Servite High in Anaheim. Kalil also participated in track & field at Servite, where he had top-throws of 13.55 meters (44 feet, 4 inches) in the shotput and 39.80 meters (130 feet, 5 inches) in the discus.
After redshirting his initial year at USC, Kalil served as backup to Tyron Smith at right tackle. He started against Boston College and performed well, and saw limited action in 11 other games (all but Arizona State) and played primarily on special teams. In his sophomore year, Kalil beat Smith to replace Charles Brown at left tackle, where he started all 13 games. He also played on the defensive line for special teams and blocked a point after touchdown against Notre Dame.
As a junior, Kalil retained his starting left tackle spot, helping the Trojans average 456.8 yards of total offense. The Trojans' offensive line only allowed an FBS-low eight sacks of quarterback Matt Barkley, none of which were allowed by Kalil. For his effort, Kalil was named to several All-American teams, while also becoming the 12th Trojan offensive lineman to win the Morris Trophy. Kalil was also semifinalist for the 2011 Lombardi Award.
Already after his sophomore year, Kalil was regarded as the best offensive tackle prospect for the 2012 NFL Draft. He declared for the draft on December 16. After a strong performance at the NFL Combine, Kalil was projected to be the No. 3 draft pick by the Minnesota Vikings. The Vikings eventually selected Kalil, but not until trading down to the No. 4 spot. They had not selected an offensive lineman in the first round since Bryant McKinnie in 2002.