Melton was selected by the Houston Rockets in the second round of the 2018 NBA draft with the 46th pick, but was traded to the Phoenix Suns before his rookie season began.

On January 25, in an 84–76 win over future #2 pick Lonzo Ball and UCLA, Melton had 13 points, 9 rebounds, 5 assists, 4 steals, and a block.

He followed this performance with a 16-point, 7 rebound, 6 assist, 6 steal, and 2 block game against future #1 pick Markelle Fultz and Washington on February 1.

Melton became the first freshman to record at least 300 points, 150 rebounds, 100 assists, 60 steals, and 35 blocks in their starting season since Dwyane Wade.

[7] On September 26, 2017, federal prosecutors in New York announced charges of fraud and corruption against 10 people involved in college basketball, including USC assistant coach Tony Bland.

[11] On August 31, Melton was traded alongside Ryan Anderson to the Phoenix Suns in exchange for Brandon Knight and Marquese Chriss.

Melton was assigned to the Northern Arizona Suns, Phoenix's development team in the NBA G League, for their first game of the season on November 3, 2018.

[18] On July 7, 2019, the Suns traded Melton, Josh Jackson, and two second round picks to the Memphis Grizzlies in exchange for Jevon Carter and Kyle Korver.

[22] On April 19, 2021, he scored a season-high 25 points, alongside eight rebounds, six assists and five steals in a 139–137 double overtime loss to the Denver Nuggets.

[23] Melton helped the Grizzlies qualify for the playoffs for the first time since 2017, and they faced the top-seeded Utah Jazz during their first-round series.

On March 26, 2022, Melton scored a season-high 24 points, alongside three rebounds, two assists and three steals, in a 127–102 win over the Milwaukee Bucks.

On June 24, 2022, Melton was traded to the Philadelphia 76ers in exchange for Danny Green and the draft rights to David Roddy.