He played college football for the University of Texas, was recognized as a unanimous All-American, and was selected by the Washington Redskins with the thirteenth overall pick in the 2009 NFL draft.

[34] Orakpo made his NFL debut and first start in the season-opener against the New York Giants and recorded two solo tackles in a 23–17 road loss.

[41] Orakpo finished his rookie year 50 combined tackles (37 solo), a career-high 11 sacks, and two pass deflections in 16 games and starts.

[44] During Week 5, Orakpo recorded three combined tackles and a season-high a two sacks on quarterback Aaron Rodgers during a 16–13 win over the Green Bay Packers.

[47] Orakpo finished his second professional season with 56 combined tackles (36 solo), 8.5 sacks, two pass deflections, and a forced fumble in 15 games and starts.

[58] Orakpo and Ryan Kerrigan returned as the starting outside linebackers to begin the regular season, along with London Fletcher and Perry Riley.

[59] During Week 2, Orakpo recorded three solo tackles and a sack before exiting the 31–28 road loss against the St. Louis Rams after tearing his pectoral muscle.

[60][61] On September 18, 2012, the Redskins officially placed Orakpo on injured reserve after confirming he would have to undergo surgery to repair his torn pectoral muscle and would miss the rest of the season.

[63] During Week 4, Orakpo recorded four combined tackles, a season-high two sacks, and broke up two passes during a 24–14 road victory against the Oakland Raiders.

[64] Three weeks later, he recorded four combined tackles, a pass deflection, and returned an interception for his first NFL touchdown during a 45–41 victory against the Chicago Bears.

[65][66] Orakpo intercepted a pass by quarterback Jay Cutler, that was intended for wide receiver Alshon Jeffery, and returned it 29 yards for a touchdown in the second quarter.

[69] Orakpo finished the season with a career-high 60 combined tackles (43 solo), ten sacks, four pass deflections, an interception, and a touchdown in 15 games and starts.

[71] On March 3, 2014, the Redskins applied their non-exclusive franchise tag on Orakpo which allowed them to match any contract offer by other teams attempting to sign him.

On October 19, 2014, Orakpo made one tackle before exiting in the fourth quarter of the Redskins' 19–17 win against the Tennessee Titans due to an injury to his right shoulder.

[77] Orakpo finished the 2014 season with 24 combined tackles (14 solo), a pass deflection, and was credited with half a sack in seven games and starts.

[84] During Week 9, Orakpo recorded four combined tackles, deflected a pass, and had a season-high two sacks on quarterback Drew Brees during a 34–28 overtime road victory against the New Orleans Saints.

[88] During Week 5, Orakpo collected a season-high six combined tackles and sacked quarterback Ryan Tannehill twice during a 30–17 road victory against the Miami Dolphins.

[90] Orakpo finished the 2016 season with 46 combined tackles (38 solo), 10.5 sacks, four pass deflections, and a forced fumble in 16 games and starts.

[92] Head coach Mike Mularkey retained Orakpo, Derrick Morgan, Wesley Woodyard, and Avery Williamson as the starting linebackers in 2017.

[93] During a Week 2 37–16 victory over the Jacksonville Jaguars, Orakpo forced a fumble off of quarterback Blake Bortles, which was recovered by teammate Erik Walden.

[98] On January 6, 2018, Orakpo started in his first career playoff game and recorded two combined tackles and 1.5 sacks during a narrow 22–21 road victory against the Kansas City Chiefs in the AFC Wild Card Round.

[99] The following week, he recorded two combined tackles as the Titans lost to the New England Patriots in the AFC Divisional Round on the road by a score of 35–14.

In 2018, Orakpo and Tennessee Titans teammate Michael Griffin opened a franchise of Gigi's Cupcakes outside Austin, Texas with their friend, Bryan Hynson.