He saw limited action with the Pistons and spent time with the Fort Wayne Mad Ants of the NBA Development League during his rookie season.

Another cousin, Kenny Manigault, played basketball for Wichita State University and was teammates with Middleton on the Amateur Athletic Union (AAU) team Carolina Celtics.

[2] Two other teammates on the Carolina Celtics accepted Division I basketball scholarships, Jamal Curry (Radford) and Devin Booker (Clemson).

Coming into his freshman year, Middleton expected to fill the three-point shooting void of departed senior Josh Carter.

Middleton's college career started slowly, connecting on 1-of-12 field goals in limited action of his first three games.

[8] After a season-ending leg injury to Derrick Roland on December 11, 2009, Middleton was forced to take a larger role in the offense and started 18 of the last 20 games.

[13] Middleton-led Texas A&M went 24–9 and lost in the NCAA Tournament round of 64 to Florida State 57–50, in a contest in which Middleton contributed 16 points.

[16] He was recognized as an All-Eighth District second-team selection by the National Association of Basketball Coaches making him eligible for the State Farm Division I All‐America teams.

[18] Prior to Middleton's junior season, head coach Mark Turgeon left to take the same position at the University of Maryland and was replaced by Billy Kennedy of Murray State.

[34] On September 21, 2016, Middleton was ruled out for six months after sustaining a left hamstring injury in preseason workouts that required surgery.

[35] On February 8, 2017, he made his season debut after missing the first 50 games with the hamstring injury, scoring five points in 15 minutes in a 106–88 loss to the Miami Heat.

[41] In game 1 of the Bucks' first-round playoff series against the Boston Celtics, Middleton had 31 points, eight rebounds and six assists in a 113–107 overtime loss.

[50] On January 28, 2020, Middleton set a new career high, scoring 51 points, making 16-of-26 shots, including 7-of-10 on 3-pointers, in a 151–131 victory over the Washington Wizards.

[54] In the postseason, Middleton and the Bucks were eliminated in the semi-finals by the eventual Eastern Conference champion Miami Heat in five games.

In game 1, Middleton capped off a 27-point, 6-rebound and 6-assist performance with a game-winning fadeaway jumper with 0.5 seconds left in overtime, to lift Milwaukee to a 109–107 victory and a 1–0 series lead.

[58] In game 6 of the Conference semi-finals against the Brooklyn Nets, Middleton dropped a playoff career-high 38 points, alongside 10 rebounds, five assists and five steals in a 104–89 victory.

[59] In game 3 of the Conference Finals against the Atlanta Hawks, Middleton tied his career-high 38 points, alongside 11 rebounds and seven assists in a 113–102 victory.

[63] In the first game of the 2021–22 NBA season, Middleton scored 20 points and recorded 9 rebounds in a 127–104 blowout win over the Brooklyn Nets.

[69] On April 20, in a game 2 loss during Milwaukee's first-round postseason matchup against Chicago, Middleton suffered a medial collateral ligament sprain,[70] which sidelined him for the rest of the playoffs.

[71] On December 3, 2022, Middleton made his return after missing the first twenty games of the 2022–23 season while recovering from off-season wrist surgery, finishing with 17 points and 7 assists during a 133–129 loss to the Los Angeles Lakers.

[77] On April 16, in the opening game of the playoffs Middleton posted 33 points, nine rebounds and four assists in a 130–117 loss against the Miami Heat.

[78] In game 5 of the series, Middleton scored 33 points, along with six rebounds and six assists but despite his effort, the Milwaukee Bucks lost 128–126 in overtime to the Heat.

[80] On November 20, Middleton scored 18 points during a 142–129 win over the Washington Wizards, and passed Sidney Moncrief to become the fourth-all-time-leading scorer in Bucks franchise history.

[81][82] On January 22, 2024, Middleton put up 26 points in a 122–113 win over the Detroit Pistons, and passed Glenn Robinson to become the third-all-time-leading scorer in Bucks franchise history.

[84] On March 24, Middleton recorded his second career triple-double, with 11 points, 10 rebounds and 10 assists during a 118–93 win over the Oklahoma City Thunder.

[85] On April 26, Middleton recorded a playoff career-best 42 points, while adding 10 rebounds and five assists, during an overtime 121–118 first-round loss to the Indiana Pacers in game 3.

In order to be there for the birth, Middleton got on a plane to Milwaukee with Bucks co-owner Marc Lasry immediately after a playoff win over the Detroit Pistons.

[93] On March 13, 2020, Middleton said he would match Giannis Antetokounmpo's $100,000 donation to the staff of the Fiserv Forum who were unable to work during the suspension of the 2019–20 NBA season because of the COVID-19 pandemic.