An impact player on the defensive side of the ball, Alexander missed most of his 2011 senior campaign with a knee injury after posting 144 tackles, 17 sacks, and six forced fumbles (three recoveries) as a junior in 2010.

Oxford finished the season 12–2, advancing the AHSAA Class 6A state semi-finals where they lost 32–22 to Marlon Humphrey's Hoover.

[7] On December 31, 2014, Alexander announced on his Twitter account his decision to forgo his senior season and enter the 2015 NFL draft.

[9] On March 27, 2015, Alexander attended LSU's pro day, but opted to stand on his combine numbers and only performed positional drills for team representatives and scouts from all 32 NFL teams, including Pittsburgh Steelers' head coach Mike Tomlin and general managers from the Minnesota Vikings, New Orleans Saints, New York Giants, New York Jets, and Steelers.

[11] At the conclusion of the pre-draft process, Alexander was projected to be a third round pick by NFL draft experts and scouts.

The Buccaneers traded their fourth (128th overall) and seventh round (218th overall) picks to the Oakland Raiders in order to move up four spots and select Alexander.

[18] Alexander entered training camp, competing for the job as the starting strongside linebacker against Danny Lansanah.

On December 7, Alexander was given a four-game ban for violating the league's policy on performance-enhancing substances and missed the last four games of the season (Weeks 14–17).

[24] Alexander finished his rookie year with 93 combined tackles (59 solo), nine pass deflections, three sacks, and two interceptions in 12 games and starts.

[26] The Buccaneers finished fourth in the NFC South with a 6–10 record and Lovie Smith was fired at the end of the season.

Two weeks later, he made seven combined tackles and returned an interception off of Case Keenum 38 yards for his first NFL touchdown during a 37–32 loss to the Los Angeles Rams.

During Week 8, Alexander recorded a season-high 14 solo tackles and broke up a pass in a 30–24 overtime loss to the Oakland Raiders.

Alexander finished his second professional season ranking fourth in the league in tackles with 145 combined (108 solo).

[29] Alexander started in the season-opener against the Chicago Bears and recorded a solo tackle, a pass deflection, and intercepted former teammate Mike Glennon during a 29–7 victory.

[32] Alexander finished his third season with 97 combined tackles (70 solo), four pass deflections, and a career-high three interceptions in 12 games and starts.

On January 16, 2018, he was named to his first Pro Bowl replacing injured Seattle Seahawks middle linebacker Bobby Wagner.

[36][37][38] During Week 1 against his former team, the Tampa Bay Buccaneers, Alexander made a helmet-to-helmet hit against former teammate Jameis Winston, and was disqualified as a result.

[41] During Week 7 against the Washington Redskins, Alexander forced a fumble on running back Adrian Peterson that was recovered by teammate Jullian Taylor in the 9–0 road victory.

[46] He helped the 49ers defeat both the Vikings and Green Bay Packers to advance to Super Bowl LIV, where he recorded a tackle and pass deflection in the 31–20 loss to the Kansas City Chiefs.

On November 2, 2020, the San Francisco 49ers traded Alexander to the Saints in exchange for a fifth-round conditional pick in the 2021 NFL draft and linebacker Kiko Alonso.