He played in the National Basketball Association (NBA) for the Atlanta Hawks, Minnesota Timberwolves, and Orlando Magic as well as for several European and Asian teams.

[1] As a junior, Payne led the Big Ten in free-throw percentage (.848) and blocked a total of 46 shots, good for sixth all-time for a Michigan State player.

[1] Payne was named to the Second Team All Big Ten, along with Michigan State teammates Keith Appling and Gary Harris.

[14] The Michigan State big man scored 41 points in a 93–78 win over Delaware, setting the pace for the 2014 NCAA Tournament.

Moreover, Payne shot 17 of 17 from the free-throw line, which set an NCAA Tournament record for most free throws made in a game without a miss.

During the 2013–14 college basketball season, Payne's friendship with Lacey Holsworth, an 8-year-old cancer patient, gained national media attention.

[15] Their friendship started when Payne met Holsworth during a team-sponsored hospital visit in 2011 and the two began to text and talk frequently afterward.

[21] He subsequently missed the first ten games of the season with the injury, and upon his return, he was assigned to the Fort Wayne Mad Ants of the NBA Development League on November 20.

[31] On March 9, 2015, while starting in place of Kevin Garnett, he had a season-best game with 16 points, and 15 rebounds in an 89–76 loss to the Los Angeles Clippers.

On January 26, 2018, he was waived by Orlando after his name surfaced in an alleged sexual assault dating back to his freshman year in college.

[42] Payne started the season 2018–19 with the Nanjing Tongxi Monkey King of the Chinese Basketball Association, where he averaged 16.9 points and 8.6 rebounds per game.

[43][44] On January 12, 2019, Payne and Panathinaikos reached an agreement that would bring the player back in Greece for a second stint with the EuroLeague club.

[53] On May 9, 2022, Payne was fatally shot in Orlando, Florida, after he and his girlfriend had travelled to the home of Lawrence Dority in an attempt to prevent a domestic dispute.