In just 26 games with the Panthers, Fitzgerald caught 161 passes for 2,677 yards and set a new Pitt record with 34 receiving touchdowns. He was the first player in school history with back-to-back 1,000-yard receiving seasons, and his 14 games with at least 100 yards receiving broke Antonio Bryant's previous all-time Panthers record of 13. Fitzgerald also holds an NCAA record with at least one touchdown catch in 18 straight games.
On July 1, 2013, Fitzgerald's #1 jersey was retired by the University of Pittsburgh. Fitzgerald is the 9th Pitt player to receive this honor.
Although Fitzgerald had played at Pitt for only two years without redshirting, he petitioned the NFL to allow him to enter the 2004 NFL Draft, as he had left his high school, Academy of Holy Angels, during his senior year to attend Valley Forge Military Academy. The NFL granted an exception to allow Fitzgerald to enter the draft, as Fitzgerald had convinced the NFL that the time he spent at the Academy, combined with his time at Pitt, was the minimum three years removed from high school to make him eligible for the draft. Although former Ohio State running back Maurice Clarett was suing the NFL at the time to overturn the rule (a case Clarett initially won, but it was later overturned on appeal), the NFL considered Fitzgerald's case separate from Clarett's.
Fitzgerald left the University of Pittsburgh after a tremendous sophomore year in which he caught 92 passes for 1,672 yards and 22 touchdowns. He was drafted third overall in the 2004 NFL Draft by the Arizona Cardinals, whose then coach, Dennis Green, knew Fitzgerald from his time as a Vikings ball boy.
In 2004, Fitzgerald had 59 receptions for 780 yards and 8 touchdowns. On December 12, 2004, Fitzgerald became the youngest player at 21 years and 110 days, to record at least 2 touchdown receptions in a single game. In 2005 he led the NFL with 103 receptions for 1,409 yards and 10 touchdowns and was named to his first Pro Bowl. Fitzgerald teamed with Anquan Boldin to create one of the most dangerous wide receiver tandems in the NFL. In 2005, they became only the third duo from the same team to each catch over 100 passes and also the third pair of teammates to top the 1,400-yard mark.
In 2006, Fitzgerald was injured and missed part of the season but still produced 69 receptions for 946 yards and 6 touchdowns. As part of his 2007 Pro Bowlseason, he caught 100 receptions for 1,409 yards and 10 touchdowns. Following the 2007 season Fitzgerald signed a four-year, $40 million contract extension with Arizona. While still under contract at the time, performance bonuses forced the team's hand into a massive extension. Fitzgerald's numbers earned him the nickname "Sticky Fingers" and "The Best Hands in the NFL" in local media.
During the NFC Championship for the 2008 NFL season, Fitzgerald tied an NFL record with three touchdown receptions in a playoff game. His three touchdown catches occurred in the first half; he became the first player in NFL history to accomplish that feat in a conference championship game. Fitzgerald also set a single postseason record with 546 receiving yards, 30 receptions, and 7 touchdown receptions, surpassing Jerry Rice's records of the 1988–89 NFL playoffs. He and the Cardinals represented the NFC in Super Bowl XLIII. During Super Bowl XLIII, Fitzgerald caught two touchdown passes in the Cardinals 27–23 loss to the Steelers. Fitzgerald followed up this performance by catching two more touchdown passes in the 2009 Pro Bowl, earning him MVP honors. After the Pro Bowl was over it was revealed that Fitzgerald had been playing at least the whole postseason with a broken left thumb as well as torn cartilage in the same hand. It is speculated that Fitzgerald has had this injury since November 5, 2008, when he showed up on the injury report with an injured thumb. After his record-breaking postseason, capped by his Pro Bowl MVP award, many analysts, including NFL Network's Jamie Dukes, regarded Fitzgerald as one of the best receivers in the NFL.
Despite having about 300 yards less than the year before, he set a personal record with 13 touchdowns in 2009. He added two more touchdown catches in the Wild Card game against the Green Bay Packers in a 51–45 win. However, the Cardinals were eliminated the next week, beaten 45–14 by the New Orleans Saints.
The 2010 season for the Cardinals was a major let down from the previous two years, as the retiring of Kurt Warner greatly affected their offense. Despite this, Fitzgerald was still able to catch 90 passes for 1,137 yards, and 6 touchdowns. After the season he was named to his 5th Pro Bowl, and his 4th in a row.
On August 20, 2011, Fitzgerald signed an 8-year $120 million deal with the Arizona Cardinals, tying him with Richard Seymour as the 5th highest paid player in the NFL. Fitzgerald would reward the Cardinals by having another stellar season, catching 80 passes for 1,411 yards and 8 touchdowns and setting a personal record of 17.6 yards per catch. Fitzgerald's accomplishments were recognized by an All-Pro second team selection as well as his 6th Pro Bowl selection.
Fitzgerald's father, Larry Fitzgerald Sr., is a sportswriter for the Minnesota Spokesman-Recorder. When he covered Super Bowl XLIII, he was believed to be the first reporter to cover his own son in a Super Bowl. Fitzgerald's mother, Carol, died of a brain hemorrhage while being treated for breast cancer in 2003. Fitzgerald also has a younger brother, Marcus Fitzgerald, who was a wide receiver for the Sacramento Mountain Lions of the United Football League.
Fitzgerald has a son named Devin. He had an order of protection filed against him by the mother of his child in October 2008 after an altercation between the two.