At only 18 years of age, Harrington was selected by the Indiana Pacers with the 25th overall pick in the 1998 NBA draft, and spent six seasons with them, primarily coming off the bench. Harrington really began to come into his own in the 2001–02 season, in which he averaged 13.1 points and 6.3 rebounds per game, but his season came to an end in a game against the Boston Celtics when he suffered a knee injury that forced him to miss the final 38 games of the season.
He made a comeback in the 2002–03 season, becoming the only Pacer to play in all 82 games that year. He averaged 12.2 points and 6.0 rebounds per game while starting in 37 games. The following season, he boosted his averages slightly to 13.3 points and 6.4 rebounds per game, and finished second in voting for the NBA Sixth Man of the Year Award. He was an integral part of the Pacers' first run to the Eastern Conference Finals since 2000.
On July 15, 2004, Harrington was traded to the Atlanta Hawks in exchange for Stephen Jackson. Harrington finally became a nightly starter, but the Hawks did not fare as successfully as the Pacers did after his departure.
On August 22, 2006, Harrington was acquired by the Indiana Pacers from the Atlanta Hawks in a sign-and-trade deal that also sent the Hawks a 2007 first round draft pick. In 2006–07, Harrington wore jersey #32 because his first choice #3 was worn by teammate Šarūnas Jasikevičius (saying it stands for "number three, and it's my second time around").
On July 15, 2010, Harrington signed a multi-year deal with the Denver Nuggets. During the 2010–11 season, he averaged 10.5 points, 4.5 rebounds, and 1.4 assists in 22.8 minutes per game. The Nuggets finished 50-32, 5th best in the Western Conference and 2nd in the Northwest Division. The Oklahoma City Thunder defeated the Nuggets in five games in the first round of the 2011 Playoffs.
On August 10, 2012, Harrington was traded to the Orlando Magic in a four-team trade which sent Dwight Howard to the Los Angeles Lakers. He only played 10 games for the Magic in 2012–13, averaging 5.1 points, 2.7 rebounds, and 1.0 assists in 11.7 minutes per game. The Magic finished with a 20-62 record, the worst record in the NBA. On August 2, 2013, Harrington was waived by the Magic.