[2] However, he was overshadowed by Oregon-bound Simione Fili of Cottonwood High School, who was labeled the best defensive lineman from Utah since Haloti Ngata.

[6] Now far over 300 pounds, Lotulelei played defensive line for the Badgers alongside James Aiono, and recorded 52 tackles with 14 tackles-for-loss, three sacks and one forced fumble in 2008.

A regular starter in 2011, Lotulelei was an All-Pac-12 Conference performer and won the Morris Trophy as the league's best defensive lineman.

A season-high seven tackles plus two pass breakup came early in the season in a 24–21 win against the school to which he had previously committed, Brigham Young.

Lotulelei's rare combination of power, snap count anticipation, instincts, quickness, and athleticism frequently drew parallels to Haloti Ngata.

[15] Lotulelei was declared ineligible to participate in the 2013 NFL Scouting Combine after an echocardiogram revealed an abnormally low ejection fraction.

[19] After further tests by cardiologists at the University of Utah, Lotulelei's condition found to be caused by a viral infection and eventually disappeared, showing "complete normalization of the heart muscle function".

He reportedly "looked strong in all the position drills", and registered 38 repetitions in the 225-pound bench press,[21] which would have tied him with Margus Hunt and Brandon Williams for the top mark at the combine.

[30] In his rookie year, Lotulelei started all 16 regular games for the Panthers, recording 42 tackles, three sacks and 23 quarterback pressures.

He was named to the All-Rookie teams by the PFWA, ESPN, ProFootballFocus, and SB Nation[34][35] Lotulelei finished 4th in AP Defensive Rookie of the Year voting.

Through the first week of the season, Lotulelei ranked among the top 10 defensive tackles in the NFL in pass rush productivity.

[38] During the final, win-or-go victory over the Atlanta Falcons in the final game of the regular season that catapulted the Panthers to back-to-back NFC South division titles, Lotulelei finished the afternoon with 2 sacks, 1 quarterback hit, 3 hurries during his pash rush opportunities on Matt Ryan while recording 4 stops on only 9 snaps against the run.

[41] Lotulelei's 2015 preseason was cut short by a stress reaction in his surgically repaired right foot and it further caused him to miss the first 2 games of the NFL season during which the Panthers were able to produce victories over the Jacksonville Jaguars and Houston Texans.

[46] On 10 September 2017, in the season opening 23–3 victory over the San Francisco 49ers, Lotulelei's teammate Wes Horton sacked quarterback Brian Hoyer and forced a fumble.

[47] In the 2017 season, he started all 16 games and recorded 1.5 sacks, 25 total tackles, three tackles-for-loss, five quarterback hits, one pass defensed, and one fumble recovery.

[49][50] The signing reunited Lotulelei with Buffalo Bills' head coach Sean McDermott, who was previously the defensive coordinator for the Carolina Panthers.

[51] Two weeks later against the Dallas Cowboys on Thanksgiving Day, Lotulelei recorded his first NFL interception, picking off a screen pass from Dak Prescott and then blocking a field goal in the same game.

[52][53] In the 2019 playoffs, Lotulelei had a key play late in the 4th quarter of the Wild-card game against the Houston Texans, stuffing quarterback Deshaun Watson on a 4th-down quarterback sneak to give the Bills the ball back, after which they drove down the field for a game-tying field goal, but Buffalo lost in overtime 19–22.

[59][60] Lotulelei is married to Fuiva (née Hola) of Draper, Utah, a former volleyball player he met at Snow College in 2008.