Harris was made captain of Leeds in his first full season at the club at the age of twenty one, and became the first Leeds skipper in a decade to lift silverware when Leeds claimed the 1999 Challenge Cup.
A superb goal-kicker, Harris broke the club record for goals in a season in 1999 with 168, he was named at stand-off in 1999's Super League IVDream Team, and broke the 2,000 career points total two years later.
Harris made his début for the Welsh side on 10 November 2001, playing against Argentina in Cardiff; Wales lost 16–30. Having played only 200 minutes of rugby union before his international début, Harris struggled, particularly with his tactical kicking. This led to a move from fly-half to inside centre, where he could be creative with less pressure.
Harris played in the 2003 Rugby World Cup in Australia where Wales lost in the quarter-finals to eventual winners, England, despite leading the game for 60 minutes. Harris won 25 Wales caps as a union player but made it clear that he wanted to return to League.
Harris wrote a book, published in October 2005, detailing his moves between codes called Iestyn Harris: There and Back – My Journey from League to Union and Back Again. Harris was part of the 2005 Bradford squad that became the first side in the history of Super League to win the Grand Final when finishing third in the final league ladder. He played for the Bradford Bulls at stand-off half back, kicking a goal in their 2005 Super League Grand Final victory against Leeds Rhinos.
Harris was Bradford captain for one year in 2006 taking over from Leeds-bound Jamie Peacock. As Super League champions Bradford faced National Rugby League premiers Wests Tigers in the 2006 World Club Challenge. Harris captained the Bulls from stand-off half, kicking five goas from six attempts in their 30–10 victory. On 10 May 2006, Harris announced he would be retiring from playing international rugby league with Great Britain, just a week after being named in a 36-strong training squad for a June 2006 Test against New Zealand. Harris, who won the last of his 15 caps against Australia in November 2005, says he wanted to concentrate on his club career. On 26 September 2006, he confirmed that he would continue to play for Wales, and was scheduled to return to the side against Scotland at the Brewery Field, Bridgend in the 2008 Rugby League World Cup qualifying match on Sunday 29 October 2006. He was forced to pull out through injury hours before kick-off. Harris kicked a club record 15 goals against Toulouse Olympique in a record 98–6 win on 19 April 2008. Harris had been linked to a player-coach role with Crusaders, but he decided to sign for National League One club Featherstone Rovers instead.
Harris signed a 2-year deal at Featherstone Rovers, as well as playing, he also took his first steps into coaching and working in the marketing department of the club. On announcement of his tenure as assistant coach to Brian Noble at Celtic Crusaders, he agreed termination of his contract at Featherstone Rovers and an immediate end to his playing career.
While still playing for Bradford, Harris was appointed Wales Assistant Coach on 18 June 2008. On 22 September 2009, Harris was appointed Wales's rugby league head coach, succeeding John Dixon. Appointed alongside Harris were the more experienced Kevin Ellis and Clive Griffiths, and the trio's first match was against England on 17 October, which they lost 48–12.
Wales qualified for the 2011 Rugby League Four Nations, and therefore won the Tournament's co-hosting rights with England. Unfortunately, as expected, Wales lost all of games, but they put up great fights. They lost by 42–4 against England, but they played well against the Kiwis at Wembley Stadium in London. Wales lost by 36–0, but New Zealand were frustrated by not being able to play their attacking football full of flair, and this was due to Harris' team's good defence. Then surprisingly, in Wales' (and Welsh legend Lee Briers final game of his international career) final game of the Tournament, Wales shocked all odds, as they had an early 8–0 lead, against world heavyweights Australia, after 14 minutes. It took Australia until just before half-time to take the lead. Harris' men would then go on to lose the game 56–14, but he still gave Lee Briers a fitting farewell.
Iestyn coached Wales in the 2013 Rugby League World Cup held in their own country and fellow British nation England. Unfortunately Iestyn's side didn't get a single win at the event, and they gave history to each of the teams that defeated them. Italy won their first World Cup match in their first appearance, USA in their annual tournament advanced to the quarter-final, and the Cook Islands won their first ever World Cup match.
In 2014, it was announced by Marwan Koukash that Harris would take over from Brian Noble as head coach at Salford Red Devils. The appointment was described as a "huge gamble". In Harris' first match in charge, Salford played away from home and defeated Bradford by 38–24.
In September 2015, after being absent from the club for two months, Salford mutually sacked Harris from his post as head coach of the club.