Considered a four-star recruit by Rivals.com, Collison was listed as the No. 16 point guard and the No. 100 player in the nation in 2005.

He was a backup to Jordan Farmar in the Bruins’ 2005–06 season, becoming the starting point guard the following season. He was awarded the MVP of the Maui Invitational Tournament in December 2006 and was named the Pacific-10 Conference Player of the Week on December 4, 2006, and again on February 18, 2007. During the 2006–07 season, Collison averaged 2.2 steals per game—the most in the Pacific-10 Conference. He also averaged 5.7 assists (2nd in the Pac-10), as well as a three-point field goal percentage of 44.7 percent.

Collison was widely considered to be one of the top point guard prospects in the 2009 NBA Draft coming out of UCLA. He was selected in the first round with the 21st overall pick by the New Orleans Hornets.

With Chris Paul out for months at two separate times during the 2009–10 season, Collison became the starting point guard. Collison handed out a Hornets rookie-record 18 assists and scored 17 points on January 30, 2010 when New Orleans ended Memphis’s 11-game home winning streak with a 113–111 overtime victory. Later on March 8, 2010, Collison broke his own record with a Hornets rookie-record 20 assists (along with 16 points) in a 135–131 victory over the Golden State Warriors. In a game against the Indiana Pacers on February 19, 2010, Collison became only the second rookie of the 2009–10 season to get a triple-double with 18 points, 13 rebounds, and 12 assists. He finished 4th in the NBA Rookie of the Year voting and averaged 18.8 points and 9.1 assists in the 37 games as a starter, but had four turnovers a contest as a starter in his first NBA season.

On August 11, 2010, the Hornets traded Collison and James Posey to the Indiana Pacers in a four-team, five-player deal that also sent Troy Murphy to the New Jersey Nets, Trevor Ariza to the New Orleans Hornets and Courtney Lee to the Houston Rockets.

On July 12, 2012, Collison and Dahntay Jones were traded to the Dallas Mavericks for Ian Mahinmi. Collison became the Mavericks’ starting point guard, replacing Jason Kidd who left as a free agent. Collison was a key player in Dallas’ 4–1 start in 2012–13, but he struggled as they lost 8 of their next 11. After starting the team’s first 14 games, Collison came off the bench for one game. He missed the next game with a sprained right middle finger, prompting Dallas to sign Derek Fisher. Fisher started in his first game with the Mavericks, while Collison remained a reserve. 14 games later, on December 27, 2012, he regained the starting job.

On July 10, 2013, Collison signed a deal with the Los Angeles Clippers. He again backed up Chris Paul, who was also on the Clippers. When Paul was out 18 games with an injured shoulder, Collison started and averaged 13.3 points and 6.5 assists in 32.6 minutes. The Clippers went 12–6 in that span, and coach Doc Rivers said the team “weathered the storm” without their All-Star point guard; he called Collison’s play “the key.” In Game 4 of the second round of the 2014 NBA Playoffs against the Oklahoma City Thunder, the Clippers overcame a 22-point deficit to tie the series at 2–2, as Collison scored 12 of his 18 points in the final quarter to help lead the team to a 101–99 win.

On July 12, 2014, Collison signed a three-year, $16 million deal with the Sacramento Kings. The Kings offered him a starting job at point guard, and the Clippers were unable to match either the deal or the playing time.

On December 27, 2014, Collison had a season-best game with 27 points and 10 assists in a 135–129 overtime win over the New York Knicks. On February 26, 2015, he was ruled out for three to six weeks with a right hip flexor. Collison was suspended for the first eight games of the 2016–17 season after pleading guilty on a misdemeanor charge of domestic battery.

On July 7, 2017, Collison signed with the Indiana Pacers, returning to the franchise for a second stint. He had knee surgery in early February 2018, returning to the Pacers’ line-up in mid-March. After gradually improving his three-point shooting throughout his career, Collison led the league with a career-best 47% 3-point percentage in 2017–18.

On December 10, 2018, in a 109–101 win over the Washington Wizards, Collison had 17 assists, his highest single-game total with Indiana. He ended the 2018–19 season with averages of 11 points and six assists.

On June 28, 2019, Collison announced his retirement from the NBA. A Jehovah’s Witness, he cited religious reasons for retiring. He had been expected to draw multiple contract offers for around $10 million per season.