He played college football for the South Carolina Gamecocks, earning first-team All-American honors in 2010.

Because of his performances, helping lead the Gamecocks to their first SEC Championship Game appearance in school history, Jeffery was selected as an All-American.

[7] In the season opener against ECU in which he caught five passes for 92 yards, Jeffery extended his active streak to 24 consecutive games with a reception.

[8] In the 2012 Capital One Bowl, Jeffery caught four passes for 148 yards and a touchdown but was ejected in the third quarter for fighting with Nebraska player cornerback Alfonzo Dennard.

[12] Jeffery made his debut against the Denver Broncos in week one of the preseason, and caught a game-high four passes for 35 yards, though the Bears lost 31–3.

[13] In the second preseason game, Jeffery was penalized for unnecessary roughness for fighting Washington Redskins cornerback DeAngelo Hall.

[15] In his regular season debut against the Indianapolis Colts, Jeffery caught a Jay Cutler pass for a 42-yard touchdown.

Although the injury did not appear to be significant, x-rays done on the following Monday determined Jeffery broke his right hand, which led to him missing a few games.

[20] In Week 15 against the Green Bay Packers, Jeffery was penalized three times for pass interference, nullifying a touchdown and two receptions of 36 and seven yards, as the Bears lost 21–13.

[23] In Week 13 against the Minnesota Vikings, Jeffery became the first player in franchise history to record two 200-yard games in the same season.

[25] After an injury to Lions receiver Calvin Johnson, Jeffery was named to the 2014 Pro Bowl.

[26] On January 17, 2014, Jeffery was named the Pro Football Writers Association's Most Improved Player.

[41] On September 13, Jeffery caught five passes for 78 yards in the season opener against the Green Bay Packers.

[43] On November 1, Jeffery caught a season-high ten passes for 116 yards and a touchdown against the Minnesota Vikings.

[44] On November 9, Jeffery caught ten passes for a season-high 151 yards against the San Diego Chargers.

[52] On September 11, Jeffery caught four passes for a season-high 105 yards in the season opener against the Houston Texans.

[61] In Week 2 on September 17 at Kansas City, Jeffery had 92 yards on 7 catches and one touchdown, his first as an Eagle, in a 27–20 loss to the Chiefs.

In the NFC Championship against the Minnesota Vikings, Jeffery caught five passes for 85 yards and two touchdowns in 38–7 victory to advance to Super Bowl LII.

The Eagles went on to defeat the New England Patriots 41–33 to give Jeffery and the franchise its first Super Bowl championship.

[66] In Week 4 of the 2018 season, Jeffery returned from his injury and recorded eight receptions for 105 receiving yards and a touchdown against the Tennessee Titans.

In the Wild Card round, Jeffery made six receptions for 82 receiving yards against his former team, the Chicago Bears.

As the Eagles were on a successful drive late in the 4th quarter, a wide open Jeffery dropped a pass from Nick Foles that fell into the hands of Saints' cornerback Marshon Lattimore.

"[70] In Week 1 against the Washington Redskins, Jeffery caught five passes for 49 yards and the first receiving touchdown of the season as the Eagles won 32–27.

[71] In Week 2 against the Atlanta Falcons, Jeffery left early in the game due to a calf injury.

[74] Jeffery suffered a hip injury in Week 9 against the Chicago Bears and was forced to miss the next two games.