Brown was consistently rated as the "best high school player" in his class, which also included high school standouts Eddy Curry and Tyson Chandler. He was the high school player of the year as a senior in Georgia. Brown finished his high school career at the historic Glynn Academy (in Brunswick, Georgia) as the school's all-time leading rebounder (1,235) and shot-blocker (605), and also finished second all-time as a scorer and he was named to the 2001 McDonald's All-American Team.
Originally signing a letter of intent to play for the University of Florida, he later declared for the 2001 NBA draft. The Washington Wizards, under team president Michael Jordan, decided to use their first overall pick on him. Following a pre-draft workout with the Wizards, it has been reported that Brown told then-Wizards coach Doug Collins, "If you draft me, you'll never regret it."
Perhaps as a result of hype and high expectations, Brown's rookie season was marred by a lack of maturity and production on the court. In his rookie year, Brown averaged 4.5 points and 3.5 rebounds per game.
However, the Wizards believed in Brown's potential. In his second season as a professional, Brown saw more action in the league. He started 20 out of the 80 games he played and the total minutes he played doubled. Brown improved his numbers, posting averages of 7.4 points and 5.3 rebounds per game. In his third season, Brown continued to improve, posting career highs in both points (10.9) and rebounds (7.4). He also demonstrated his great potential during a game against the Sacramento Kings, during which he registered 30 points and 19 rebounds.
After his first three years in Washington, Brown rejected a five-year, $30 million contract offer, electing instead to test the free agent market when his contract expired after the season. In his fourth season, Brown was limited to 42 games due to injuries. His highest-scoring game of the season was 19 points, compared to his season-high of 30 the year before, and he averaged 7.0 points per game. Late in the season, criticism increased; he feuded with Gilbert Arenas, other teammates, and his coach Eddie Jordan.
On August 2, 2005, Brown and Laron Profit were traded to the Lakers in exchange for Caron Butler and Chucky Atkins. This move was met with some controversy from fans who disliked Brown's reputation and his label as an "under-achiever." In the beginning of the season, he averaged just above 6 points and 6 rebounds.
On December 26, 2005, he played his first game at the Washington Wizards' MCI Center (now known as Capital One Arena) as a Laker. The sold-out crowd of 20,173 fans loudly booed him upon entering the game and whenever he touched the ball. In the second quarter, Brown was looking the other way when teammate Sasha Vujačić threw a pass his way. The ball bounced off his head and landed out of bounds, which was met with loud cheers from the crowd. Brown called the reception "weak" and stated that "they should be cheering that I'm gone." The Wizards won the game 94–91.
When Lakers center Chris Mihm went down with a season-ending ankle injury on March 12, 2006, Brown took over the starting center position. During his stint as a center, he raised his averages from 6.1 points and 6.3 rebounds to 12.3 points and 9.1 rebounds and started every game for the Lakers in the playoffs. Brown became a central part of the Lakers seven-game series with the Phoenix Suns. Although they ended up losing the series, it had appeared that Kwame Brown's potential was beginning to show. The surprising consistency Brown showed while playing center prompted Phil Jackson to make Brown the starting center in the 2006–2007 season. Brown was injured at the beginning of the season and Mihm was also out with injury for the whole season, so the starting job at center was given to the young Andrew Bynum. After playing the majority of the minutes at center despite the bench role, he was given the starting job in early December. Brown again became injured in the 2007–08 season which allowed Bynum to start again at the center position where he flourished until being traded to the Philadelphia 76ers in 2012. However, when Bynum suffered a knee injury that appeared to jeopardize the Lakers' playoff chances, Brown regained his starting position. As a starter, Brown disappointed many Laker fans, with his lackluster performance and apparent lack of focus during games, highlighted by one game where he missed an open dunk and registered more turnovers (7) than rebounds (6) en route to a Lakers loss. Though Kobe Bryant stuck by his teammate after the game and rebuked Lakers fans who booed Brown, it increasingly appeared that the chances that Brown would realize his potential were diminishing and with them the Lakers' chances of making the playoffs that year.
On February 1, 2008, Brown was traded along with Javaris Crittenton, Aaron McKie, the draft rights to Marc Gasol, and the Lakers' 2008 and 2010 first-round draft picks for Pau Gasol and a second-round pick in 2010. On July 1, 2008, the Memphis Grizzlies chose not to sign Brown to a new contract, making him an unrestricted free agent.
On July 28, 2008, ESPN.com reported that the Pistons signed Brown to a two-year deal worth $8 million, with the second year a player option.
On August 23, 2010, Brown signed a one-year deal with the Bobcats.
On December 14, 2011, Brown signed a one-year, $7 million contract with the Warriors.
On March 13, 2012, Brown, along with Monta Ellis and Ekpe Udoh, was traded to the Milwaukee Bucks in exchange for Andrew Bogut and Stephen Jackson. Brown never appeared in a game for the Bucks.
On July 20, 2012, Brown signed a two-year contract for nearly $6 million with the Philadelphia 76ers. After sustaining a right hamstring strain in September 2013, Brown was waived by the 76ers on November 20 before appearing in a game for them in the 2013–14 season.
After removing himself from the game for three years, Brown signed with player agency, Interperformances, on August 22, 2016 in an attempted comeback.
On April 30, 2017, Brown was the fifth overall pick in the inaugural draft of the BIG3 basketball league.