While attending Campbelltown St. Gregory’s College, Hoffman played for the Australian Schoolboys team in 2002.

Hoffman started his NRL career with the Melbourne Storm in 2003. In 2006, his improving form led to him being selected for the New South Wales City Origin side for the first time. It also earned him the Storm’s Forward of the Year award. In addition, he was named in the second row for Melbourne Storm’s team of the decade.

Following the 2006 NRL Grand Final loss to the Brisbane Broncos, Hoffman sat in the middle of Telstra Stadium in tears, an image which was printed in newspapers all around Australia.

In 2007, Hoffman was part of the Melbourne team which won the Grand Final, defeating Manly by 34–8. He played in the 2009 NRL Grand Final victory over the Parramatta Eels, scoring the opening try. In 2010, both premierships which Hoffman won with Melbourne were stripped due to the club’s breaches of the salary cap between 2006-2010.

He was named as the 18th man for Australia in the 2007 ANZAC Test against New Zealand. In October, 2007, he was selected in the run-on side for the Centenary Test against New Zealand in Wellington.

In 2008, Hoffman was named in the New South Wales starting side in all three Origin matches.

In August 2008, he was named in the Australia national rugby league team preliminary 46-man Kangaroos squad for the 2008 Rugby League World Cup.

He was selected for City in the City vs Country match on 8 May 2009.

In July 2010, Hoffman signed with Super League club Wigan Warriors, where he was given the #16 shirt and replaced Phil Bailey at second-row.

He then featured in the 2011 World Club Challenge where Wigan lost 15–21 to St George Illawarra Dragons in their first home game of the season.

Hoffman played in the 2011 Challenge Cup Final victory over the Leeds Rhinos at Wembley Stadium, playing as a second-row forward, helping the side to defeat Leeds 28-18.

Hoffman signed a new deal to return to the NRL and the Melbourne Storm in 2012. He played in their 2012 Premiership victory over Canterbury-Bankstown, scoring the first try.

He set up the first try for teammate Billy Slater in the 2013 World Club Challenge victory over Leeds.

On 7 May 2014 Hoffman announced that he had signed a three-year deal with the New Zealand Warriors, worth an estimated $1.6 million.

In April 2015 Hoffman played his 250th NRL career game against his former club Melbourne Storm at AAMI Park.

On 17 February 2016 Hoffman was named the new club captain, after incumbent captain Simon Mannering stepped down from the role. Hoffman is the second Australian to have captained the New Zealand club, after Steve Price.

On 1 February 2017, new Warriors coach Stephen Kearney announced that Hoffman would be replaced as captain and would not be re-signed for the 2018 season.

On 10 October 2017 the Melbourne Storm announced that Hoffman will return to the club on a 1-year deal that will see him end his playing career at the club. On Tuesday the 3rd of July Hoffman publicly announced that he was retiring at the end of the 2018 NRL season.