Despite being recruited by Florida State, Kansas and Houston, Lewis bypassed college and opted for the 1998 NBA Draft, wherein he was selected by the Seattle SuperSonics with the third pick of the second round (32nd overall). At the time of his selection, he was the last player remaining in the "green room", where fifteen of the top draft prospects sit until their selection.
Lewis has twice been named an All-Star, in the 2004–05 season and in 2008–09. In 2001, Lewis was selected to play for the USA in the Goodwill Games, in which they won the gold medal. On October 31, 2003, Lewis scored 50 points to pass Clyde Drexler (41 points) for the most points scored in a single game while playing in Japan. Lewis holds the SuperSonics' record for most three-pointers made, having passed Dale Ellis for second place on November 22, 2005, and Gary Payton for first place on March 13, 2007, when Lewis made his 918th three-pointer in the first quarter of a game against the Detroit Pistons.
After playing his first nine seasons for the Seattle SuperSonics, Lewis joined the Orlando Magic, having agreed to a six-year sign-and-trade deal worth $118 million on July 11, 2007. On May 25, he had opted out of the last two years of the seven-year, $60 million deal he signed before the 2002–03 season. The final two years of his contract were worth a guaranteed $21 million.
In his first season with the Orlando Magic, Lewis was moved from his usual small forward position to power forward. That year, he made 53 more three-pointers than he had in his career. During the playoffs, the Magic reached the second round, with Lewis contributing a 33-point performance against the Detroit Pistons in Orlando's only win of the series. Lewis was the Magic’s top scorer in the playoffs and set personal records in points, rebounds, and assists.
Lewis started the 2008–09 season as the team's second leading scorer, earning an appearance in the 2009 NBA All-Star Game. In the 2009 NBA Playoffs, Lewis hit a game-winning shot in the first game of the Eastern Conference Finals against the Cleveland Cavaliers, what he called the biggest shot of his career. The Magic won the series and advanced to the NBA Finals, where they were defeated by the Los Angeles Lakers in five games.
Over his career, Lewis holds an average of 16.1 points per game, with his career high of 22.4 points per game coming in 2006–07.
On August 6, 2009, Lewis was suspended without pay for the first ten games of the 2009–10 season after testing positive for a banned substance.
On December 18, 2010, Lewis was traded to the Washington Wizards for Gilbert Arenas.
New Orleans Hornets
On June 20, 2012, Lewis, along with the 46th pick of the 2012 NBA Draft (Darius Miller), was acquired by the New Orleans Hornets in a trade that sent Trevor Ariza and Emeka Okafor to the Wizards.
On June 30, the Hornets bought out Lewis' contract, making him a free agent.
On July 11, 2012, Lewis signed with the Miami Heat on a 2-year, $2.8 million deal and was reunited with former Seattle teammate Ray Allen. He won his first championship on June 20, 2013 when the Heat defeated the San Antonio Spurs in a seven game series.