Mills was selected by the Portland Trail Blazers with the 55th overall pick in the 2009 NBA draft after playing two years of college basketball for the Saint Mary's Gaels.

[20] In 2005, he made a strong impression at the Australian Olympic Youth Festival, an event considered to be a showcase for future elite sporting talents.

In April, Mills was a member of the World Junior Select Team that competed against the United States in the Nike Hoop Summit.

[23][24] Mills was named the 2006 SEABL U/21 Australian Youth Player of the Year, averaging 18.1 points and 3.9 rebounds per game and helping the AIS to a 16–10 regular season record.

[24] Also in 2006, Mills was the youngest athlete selected in the 22-man extended Australian Boomers squad ahead of the 2006 FIBA World Championship.

The Deadlys Awards honor Aboriginal and Torres Strait Islanders achievements in sports, music, entertainment and community.

[27] As a sophomore in 2008–09, Mills averaged 18.4 points, 3.9 assists, 2.4 rebounds and 2.2 steals in 32.1 minutes and was named WCC Player of the Week twice (24 November and 8 December).

[29] On 9 July 2009, Mills fractured the fifth metatarsal in his right foot during practice and was subsequently ruled out of the NBA Summer League.

He scored in double figures 10 times and posted what was a career-best 23 points in Portland's regular-season finale on 13 April against Golden State.

[37]Due to the 2011 NBA lockout, Mills returned to Australia to play in the National Basketball League (NBL).

With the NBA lockout ending on 8 December 2011, Mills wanted to return to the Portland Trail Blazers, but the Chinese Basketball Association could not guarantee that he would receive FIBA clearance until March.

[45] On 26 April 2012, Mills set career highs with 34 points and 12 assists for his first NBA double-double in a 107–101 win over the Golden State Warriors.

[46] Mills posted the highest single-game score by an Australian in the NBA, surpassing Andrew Bogut's 32 points in January 2010.

[49] In the Spurs' second-last game of the regular season on 15 April 2013, Mills scored a season-high 23 points in a 116–106 loss to Golden State.

[52] Mills appeared in a team-high 81 games, including two starts, averaging 10.2 points, 2.1 rebounds and 1.8 assists in a career-high 18.9 minutes.

In game 5 of the NBA Finals, Mills scored 14 of his 17 points in the third quarter to help lift the Spurs to a 104–87 series-clinching win.

[56][57] On 25 April 2017, Mills scored a postseason-high 20 points on 5-for-7 shooting in a 116–103 win over the Memphis Grizzlies in game 5 of their first-round series.

[59][60] On 4 December 2017, in a 96–93 win over the Detroit Pistons, Mills became the third Spur to have made 500 three-pointers as a reserve; the others are Manu Ginóbili and Matt Bonner.

[61] On 18 December 2017, in a 109–91 win over the Los Angeles Clippers, Mills became one of only three Spurs in franchise history to have scored 3,000 career points as a reserve; the others are Ginóbili and Malik Rose.

[62] On 25 February 2018 against the Cleveland Cavaliers, Mills climbed into fourth place on the Spurs' list of all-time three-pointers made.

[66] Also as of December 2020, only two NBA players—Udonis Haslem of the Miami Heat and Stephen Curry of the Golden State Warriors—had been with their respective teams longer than Mills had been with the Spurs.

[69] On 19 October, Mills made his Nets debut, scoring 21 points on 7-of-7 shooting from deep in a 127–104 loss to the Milwaukee Bucks.

[75] On the NBA Christmas game, Mills tied his career high with 34 points on 8-for-13 from three in a 122–115 win over the Los Angeles Lakers.

[84] On 1 February 2025, Mills was traded to the Los Angeles Clippers alongside Drew Eubanks in exchange for Mo Bamba, P. J. Tucker, a 2030 second-round pick and cash considerations.

[86] Mills became the third Indigenous basketball player to play for Australia behind Olympians Michael Ah Matt (1964) and Danny Morseu (1980–84).

[7] The following year, he played for Australia at the FIBA Diamond Ball tournament and represented his country at the Beijing Olympics, where he averaged 14.2 points per game.

[91] His performance also earned him honours as the shooting guard in the Tokyo 2020 All Star Five for the men's Olympics basketball tournament.

[93] He finished the tournament as Australia's second-leading scorer just behind Josh Giddey, scoring 66 points to bring his career total to 567.

[94] Mills is known for his three-point shooting,[95][96] his commitment to the team culture of the San Antonio Spurs[97] and the Boomers,[90] his enthusiasm,[98][99] and his leadership qualities.