He spent two stints with the Baltimore Ravens and has also played one season each for the Minnesota Vikings, Las Vegas Raiders, Indianapolis Colts, and Chicago Bears.

[14] Throughout training camp, he competed for the starting defensive end position against Dante Fowler, Chris Smith, and Jared Odrick.

Head coach Gus Bradley named him the backup defensive end behind starters Fowler and Odrick to begin his rookie season.

The following week, he earned his first NFL start, as the Jaguars opted to start him at right defensive end over Dante Fowler, and recorded three combined tackles, forced the first fumble of his career, and made his first NFL sack on Philip Rivers in the Jaguars' 38–14 loss at the San Diego Chargers.

[16][17] On October 2, Ngakoue made a season-high four solo tackles and recorded his first NFL interception on quarterback Andrew Luck after the pass was deflected by defensive end Dante Fowler during a 30–27 victory over the Indianapolis Colts.

In the season finale on January 1, 2017, he collected two solo tackles and made his eighth career sack on Luck in a 24–20 loss to the Colts.

Ngakoue finished his rookie year with 22 combined tackles (19 solo), eight sacks, two pass deflections, an interception, and a forced fumble in 16 games and 15 starts.

Ngakoue entered training camp competing to maintain his starting defensive end role against newly acquired free agent Calais Campbell and Dante Fowler.

His first forced fumble came in the second quarter and was on quarterback Tom Savage and was recovered by teammate Abry Jones, which set the Jaguars up for a touchdown scoring drive.

During Week 16 against San Francisco 49ers, Ngakoue collected two solo tackles and made his 12th sack of the season on quarterback Jimmy Garoppolo in the 44–33 road loss.

The Jaguars' defensive line became dominant throughout the season with the key additions of Calais Campbell (during free agency) and Marcell Dareus (a midseason trade acquisition).

In the playoffs, Ngakoue recorded four tackles, a pass deflection, and a sack before the Jaguars lost to the New England Patriots in the AFC Championship Game by a score of 24–20.

[26] In week 4 against the New York Jets, Ngakoue recorded his first sack of the season on rookie quarterback Sam Darnold during the 31–12 win.

[29] In week 17 against the Texans, Ngakoue recorded a season high 5 tackles and sacked Deshaun Watson 1.5 times during the 20–3 loss.

[33] In week 7 against the Cincinnati Bengals, Ngakoue intercepted a pass thrown by Andy Dalton and returned it 23 yards for a touchdown during the 27–17 win.

[41] On April 20, 2020, Ngakoue got in a lengthy Twitter argument with Tony Khan, the team owner's son, because the Jaguars would not trade him.

[52] On March 16, 2022, Ngakoue was traded to the Colts in exchange for cornerback Rock Ya-Sin after the Raiders signed Chandler Jones.