His collegiate basketball career ended in his first season with a tear of his anterior cruciate ligament (ACL) at the University of Kentucky.

[11] In addition to his high school career, Noel also played AAU basketball on the same team as future Sixers teammate Michael Carter-Williams.

[12] Shortly before his high school graduation, an article in The New York Times described Noel as being hailed as one of the best shot blockers of his generation, although he was also described as having unrefined offensive skills.

[13] Since Noel was well known for his elite shot blocking abilities, fans and the media had high expectations for him to fill the shoes of Anthony Davis, who had just led the Kentucky Wildcats to a national championship in the previous season, was the 2011–2012 National Player of the Year in the NCAA, and set a Kentucky and NCAA freshman single-season block record with 186.

[15] On January 12, 2013, although Kentucky lost the game against Texas A&M, Noel recorded 15 points, 11 rebounds, 7 blocks, 6 assists, and 4 steals.

Although he recorded only two points, Ole Miss coach Andy Kennedy said in the post-game press conference that "[Noel] was the difference in the game" and that he is "an incredible defensive presence."

Ole Miss senior forward Murphy Holloway added that he believes Nerlens Noel is the "best shot blocker [he has] played against", including Anthony Davis.

The Wildcats' 6 ft 11 in (2.11 m) center was joined by UNLV Runnin' Rebels' Anthony Bennett, UCLA Bruins's Shabazz Muhammad, Oklahoma State Cowboys's Marcus Smart and Kansas Jayhawks's Ben McLemore on the Freshman All-America team.

[40] On October 22, 2016, Noel was ruled out for three to five weeks due to an inflamed plica above his left knee that required surgery.

[44] On January 24, 2017, while making his first start of the season in place of the injured Joel Embiid, Noel scored a season-high 19 points, along with three blocks, in a 121–110 win over the Los Angeles Clippers.

[45] On February 23, 2017, Noel was traded to the Dallas Mavericks in exchange for Justin Anderson, Andrew Bogut and a 2017 protected first-round pick.

[47] On March 3, 2017, in his first start for the Mavericks, Noel tied a career high with 17 rebounds while scoring 15 points in a 104–100 win over the Memphis Grizzlies.

[48] On June 23, 2017, the Mavericks tendered a $4.1 million[49] qualifying offer to make Noel a restricted free agent.

[51] In the Mavericks' season opener on October 18, 2017, Noel had 16 points, his most since joining Dallas, and 11 rebounds in a 117–111 loss to the Atlanta Hawks.

[53] He subsequently missed 42 games, returning to action on February 28, 2018, against the Oklahoma City Thunder, recording four points, three rebounds and four fouls in 16 minutes in a 111–110 overtime loss.

[60] On January 8 against the Minnesota Timberwolves, Noel was taken off the court on a stretcher in the third quarter after taking an elbow in the face and hitting the floor hard while contesting a dunk by Andrew Wiggins.

[74] On July 11, 2022, Noel was traded, alongside Alec Burks, to the Detroit Pistons in exchange for the draft rights to Nikola Radičević and a 2025 protected second-round pick.

[75] Noel made his Pistons debut on October 31, recording two points, four rebounds and two assists in a 110–108 loss to the Milwaukee Bucks.