Phillips was selected in the second round of the 1999 MLB draft by the Montreal Expos as a shortstop after signing a letter of intent to play both baseball and football at the University of Georgia. He instead signed with the Expos on June 21, 1999.

After several years in the Expos farm system, Phillips was part of a six-player trade that sent him from the Montreal Expos to the Cleveland Indians on June 27, 2002. Phillips was dealt with Grady Sizemore, Cliff Lee, and Lee Stevens in exchange for Bartolo Colón and Tim Drew.

Phillips attended Redan High School in Stone Mountain, Georgia, where he played basketball and baseball. His #7 at Redan was retired by the school in December 2003. He was the star baseball player at his high school. Phillips’ favorite baseball player growing up was Cincinnati Reds shortstop Barry Larkin.

In 2003, Phillips won the starting job at second base for the Indians. During the season, he had a season-high six-game hitting streak. Against the Detroit Tigers on May 20, he hit the first three-run walk-off home run of his career. After that he went 0-for-29 and was sent down to the Triple-A Buffalo Bisons after the All-Star break. He was recalled soon after that due to an injury to one of his teammates and finished the season with a .208 average, six homers, 33 RBIs and four stolen bases. Phillips also totaled a .981 fielding percentage.

In 2004, he started the season in Buffalo. He hit .303 with 14 stolen bases on the season and recorded 18-game and 16-game hitting streaks. In the minor league play-offs, Phillips hit .308. He joined the Indians at the end of the season and played six games for them.

On April 7, 2006, Cleveland’s frustration with Phillips’ slow progress peaked and he was traded to the Cincinnati Reds for a player to be named later (pitcher Jeff Stevens). He made an immediate impact, starting the season by being named NL Player of the Week the same month he was acquired by the Reds, hitting .452 (14–31) with 3 home runs and 17 runs batted in for the week of April 17–23. Phillips’ 17 RBI were the most for an NL Player of the Week since Sammy Sosa had 19 RBI the week of August 4–10, 2002. Phillips had his first career grand slam that month and 16 straight stolen bases. leading the Reds in hits (148) and multi-hit games (36). He also led all National League second basemen in stolen bases with 25. He produced two 9-game hitting streaks over the season and ended with a batting average of .276, 17 home runs and 75 RBI.

In 2007, Phillips hit 30 home runs and stole 32 bases to become the first Reds second baseman to join the 30–30 club and just the third 30–30 Red, joining Eric Davis (37 HR, 50 SB in 1987) and Barry Larkin (33 HR, 36 SB in 1996). He also joined Alfonso Soriano as just the second baseman in the 30–30 club.

In the fourth inning on August 1, 2007, game, against John Lannan of the Washington Nationals Phillips stole two bases on one pitch while the Nationals had a shift on Adam Dunn. On August 30, Phillips made the play of the month to win the game for the Reds against the Pittsburgh Pirates. With the Reds winning 5–4 in the bottom of the 9th, Nate McLouth of the Pirates hit a single into right field. The runner from second, Josh Phelps, appeared likely to score but Phillips grabbed the ball in shallow right field bare-handed and threw Phelps out at home plate to win the game. On September 5, he hit his 28th home run of the season, breaking the Reds’ single-season record for home runs by a second baseman, formerly held by Joe Morgan. On September 26, 2007, Phillips hit his 30th home run of the season.

Phillips received a four-year, $27 million contract extension on February 15, 2008, instead of going to arbitration.

On April 2, 2008, Phillips hit his first home run of the season against the Arizona Diamondbacks. At the All-Star Break, Phillips was batting .287 with 15 home runs, 58 RBI, 18 stolen bases, and 18 doubles. He ended the season batting .261/.312/.442 with 21 home runs and 23 stolen bases.

Phillips won his first gold glove in 2008, leading National League 2nd basemen with a .990 fielding percentage having made just 7 errors in 706 chances, in addition to a 78-game error-less streak. He also won a Fielding Bible Award as the top fielding second baseman in MLB.

In 2009, Phillips hit .276/.329/.447, with 30 doubles, 20 home runs, 98 RBI and 25 stolen bases.

In 2010, Phillips had his first All-Star season. He finished the season batting .275, with 18 homers, 59 RBI, and 16 stolen bases.

On November 10, 2010, it was announced that Phillips had won the second Gold Glove of his Major League career.

The 86th All-Star Game was played at Great American Ball Park, and Cardinals catcher Yadier Molina was selected to play. In the Reds’ clubhouse for the All-Star Game, he was assigned Phillips’ locker. Since the brawl between the Cardinals and Reds in 2010, the two mended their schism, and Molina has a photograph of their families together. When informed of whose locker he was using, he replied, “This is Phillips’ locker? How about that? I’ll have to write something to him.” However, during pregame roster introductions, Reds fans booed all six Cardinals players in jest who were selected, including Molina, and even former Cardinal Albert Pujols, who was then with the Los Angeles Angels of Anaheim. Phillips finished the season hitting .294 (16th in the National League) with 173 hits (8th in the NL), 12 home runs, 70 RBI, and 23 stolen bases (10th in the NL).

On May 3, 2011, against the Houston Astros, Phillips threw out speedy Jason Bourgeois by picking up the ball barehanded as it rolled to him and throwing it to first baseman Joey Votto between his legs to record the out.

On November 1, 2011, it was announced that Phillips had won the third Gold Glove of his major league career. His fielding percentage for the season was .992 in 721 chances. The next day, it was announced that Phillips had won the first Silver Slugger of his Major League career. He hit an even .300 with 183 hits, 38 doubles, 2 triples, 18 homers, and 82 RBI. His on-base percentage was .353.

On April 10, 2012, it was announced that Phillips and the Reds had agreed to a 6-year, $72.5 million contract, through the 2017 season. Phillips was represented in contract negotiations by ACES Inc. When the All-Star game roster was announced on July 1, Phillips was not amongst those voted in by either fans or National League players and coaches. Reds manager Dusty Baker took exception at retired St. Louis Cardinals manager but the National League’s All-Star Game manager Tony La Russa, claiming Phillips and fellow Reds teammate Johnny Cueto were left off the roster because they were at the heart of an on-field fight involving Baker’s Reds and La Russa’s Cardinals in 2010. Baker stated “it just kind of looks bad that Johnny and Brandon were at the center of the skirmish between us and the Cardinals. Some of the Cardinals that aren’t there any more are making some of the selections.” Phillips, who was hitting just under .290 with 10 HR and 46 RBI at the time the selections were announced, declined to comment on the matter. USA Today’s Mike Jones mentioned the large number of votes for San Francisco Giants players, including Pablo Sandoval (.300, 6 HR, 25 RBI) who was named the All-Star game’s third baseman over New York Mets’ David Wright (over .350, 9 HR, 50 RBI) was responsible for “taking away an infield spot.”

In 2012, Brandon Phillips had a .281 batting average, 18 home runs, and 77 runs batted in. He did not win a Gold Glove for the first time since 2009. He batted .375 in the National League Division Series versus the San Francisco Giants, despite their loss of the series.

On August 28, Phillips was moved to the second spot in the lineup, and Jay Bruce became the cleanup hitter. While hitting second in 2013, he hit .240 with 2 HR and 6 RBI in 23 games. In 127 games while hitting 4th, he hit .265/.310/.396 with 16 HR and 96 RBI. In 151 games in 2013, he hit .261 with 18 HR and 103 RBI. He won a Gold Glove, having a .987 fielding percentage with 9 errors.

On October 23, 2014, he was nominated for his potential 5th Gold Glove for second base.

On October 29, 2015, he was named a finalist for the Gold Glove for second base.

In 2016, Phillips appeared in 141 games, batting .291 with 11 home runs and 64 RBIs. He also stole 14 bases while being caught eight times.

On February 12, 2017, Phillips waived his no-trade clause and was traded to the Atlanta Braves in exchange for minor league pitchers Andrew McKirahan and Carlos Portuondo. The Reds also sent $13 million in the deal, leaving the Braves to pay $1 million of Phillips’ remaining salary. He made a late-season position switch to third base to facilitate the promotion of Ozzie Albies to the major leagues. On August 30, Phillips hit a bloop single to drive in Ender Inciarte for his 2,000th career hit. In 120 games for the Braves, Phillips batted .291 with 11 home runs and 52 RBIs.

On August 31, 2017, Phillips was traded to the Los Angeles Angels for cash considerations and Tony Sanchez. In 24 games played with the Angels, Phillips had a slash line of .255/.269/.382 in 102 at bats.

On June 27, 2018, Phillips signed a minor league contract with the Boston Red Sox, and was assigned to the Triple-A Pawtucket Red Sox. Phillips appeared in 38 games with Pawtucket and six games with the Class A Short Season Lowell Spinners, batting a combined .304 with five home runs and 26 RBIs.

On June 25, 2019, Phillips signed with the Vallejo Admirals of the independent Pacific Association. The team is managed by his younger brother P.J. Phillips. Phillips played four games for the Admirals before being granted his release.

On July 15, 2019, Phillips signed with the Diablos Rojos del México of the Mexican League. During the season he played in 36 games. He batted .267/.327/.420 with 35 hits in 131 at bats. He had 3 home runs, 11 doubles and 15 RBIs. Phillips elected free agency on October 5, 2019.

In July 2020, Phillips played in 8 games for the Baseball Brilliance of the Yinzer Baseball Confederacy. Phillips had 5 hits in 35 plate appearances for the Brilliance, with a .152/.200/.333 batting line. One of those 5 hits included a July 11 home run against the Steel City Slammin’ Sammies at Washington Wild Things Park.

On August 19, 2020, Phillips joined the Lexington Legends in their Battle of the Bourbon Trail series. On August 22, Phillips hit a walk-off homer for the Legends, his third homer in three games for the team.