As a freshman in 2005, he appeared in 11 games (nine starts). He recorded 11 receptions for 128 yards and one touchdown. In 2006, as a sophomore, he started all 13 games. He recorded 24 receptions for 310 yards and four touchdowns and was an All-Big 12honorable mention. As a junior in 2007, he started all 13 games. He recorded 35 receptions for 540 yards and four touchdowns. As a senior in 2008, he recorded 42 receptions for 472 yards. During his career he recorded 112 receptions for 1,450 yards and nine touchdowns.
Pettigrew was selected in the first round (20th overall) of the 2009 NFL Draft by the Detroit Lions. The pick used to select Pettigrew was originally acquired by the Lions in a trade that sent Roy Williams to the Dallas Cowboys. On July 31, 2009, the Detroit Lions signed him to a five-year, $14.60 million contract with $9.4 million guaranteed and a signing bonus of $5.09 million.
The best game of his rookie season came on November 22 against the Cleveland Browns: he caught six passes for 72 yards, including the game-winning touchdown. Pettigrew suffered a knee injury during the opening drive of the Lions' annual Thanksgiving Day game in Detroit. The next day, an MRI revealed he would require season-ending surgery. On December 1, 2009, Pettigrew was officially placed on injured reserve and missed the rest of the 2009 season. He finished the season with 30 receptions for 346 yards and two touchdowns.
In 2010, he recorded 71 receptions for 722 yards and four touchdowns. His 71 receptions and 722 receiving yards were both third best among tight ends. For the 2011 season, he recorded 83 receptions for 777 yards and five touchdowns. In 2012, he recorded 59 receptions for 567 yards and three touchdowns. For the 2013 season, he recorded 41 receptions for 416 yards and two touchdowns.
On March 14, 2014, the Lions signed Pettigrew to a four-year, $12 million free-agent contract with $8 million guaranteed and a signing bonus of $4 million. For the 2014 season, he recorded 10 receptions for 70 yards.
In a December 13, 2015, game against the St. Louis Rams, Pettigrew suffered a torn ACL. He was placed on injured reserve on December 15. For the 2015 season, he recorded seven receptions for 67 yards and one touchdown.
Pettigrew started out the 2016 on the PUP list to recover from his torn ACL the previous season. He was moved to the reserve/non-football injury list on December 6, 2016. Days later the Lions cleared out his locker, indicating that the team could be moving on without him. He was officially released by the Lions on December 9, 2016.